Clinicopathological features of cytokeratin 5-positive pulmonary adenocarcinoma.

Cytokeratin 5 (CK5) is a marker for pulmonary squamous cell carcinoma; however, CK5 is sometimes present in pulmonary adenocarcinoma (ADC), and there is insufficient information regarding the clinicopathological features of CK5-positive ADC. We aimed to explore the clinicopathological characteristics of CK5-positive ADC using immunohistochemistry. We prepared the following two cohorts: a resected cohort containing 220 resected tumours for primarily studying the detailed morphological characteristics, and a tissue microarray (TMA) cohort containing 337 samples for investigating the associations of CK5 expression with other protein expressions, genetic and prognostic findings. CK5-positive ADC was defined to have ≥ 10% tumour cells and presence of CK5-positive tumour cells in the resected and TMA cohorts, respectively. CK5-positive ADCs were identified in 91 (16.3%) patients in the combined cohort. CK5-positive ADCs had male predominance (P = 0.012), smoking history (P = 0.001), higher stage (P < 0.001), histological high-grade components (P < 0.001), vascular invasion (P < 0.001), mucinous differentiation (P < 0.001), spread through airspaces (P < 0.001), EGFR wild-type (P < 0.001), KRAS mutations (P < 0.001), ALK rearrangement (P < 0.001) and ROS1 rearrangement (P = 0.002). In the resected cohort, more than half the CK5-positive ADCs (19 cases, 65.5%) showed mucinous differentiation; the remaining cases harboured high-grade components. In the TMA cohort, CK5-positive ADCs correlated with TTF-1 negativity (P = 0.002) and MUC5B, MUC5AC and HNF4alpha positivity (P < 0.001, 0.048, < 0.001). Further, CK5-positive ADCs had significantly lower disease-free and overall survival rates than CK5-negative ADCs (P < 0.001 for each). Additionally, multivariate analysis revealed that CK5 expression was an independent poor prognostic factor. CK5-positive ADCs showed aggressive clinical behaviour, with high-grade morphology and mucinous differentiation.

2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection.

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

The pharmacokinetics of dexmedetomidine administered as a constant rate infusion in horses.

Dexmedetomidine, the most selective α2-adrenoceptor agonist in clinical use, is increasingly being used in both conscious and anaesthetized horses; however, the pharmacokinetics and sedative effects of this drug administered alone as an infusion are not previously described in horses. Seven horses received an infusion of 8 µg dexmedetomidine/kg/h for 150 min, venous blood samples were collected, and dexmedetomidine concentrations were assayed using liquid chromatography-mass spectrometry (LC/MS) and analyzed using noncompartmental pharmacokinetic analysis. Sedation was scored as the distance from the lower lip of the horse to the ground measured in centimetre. The harmonic mean (SD) plasma elimination half-life (Lambda z half-life) for dexmedetomidine was 20.9 (5.1) min, clearance (Cl) was 0.3 (0.20) L/min/kg, and volume of distribution at steady-state (Vdss ) was 13.7 (7.9) L/kg. There was a considerable individual variation in the concentration of dexmedetomidine vs. time profile. The level of sedation covaried with the plasma concentration of dexmedetomidine. This implies that for clinical use of dexmedetomidine constant rate infusion in conscious horses, infusion rates can be easily adjusted to effect, and this is preferable to an infusion at a predetermined value.

Impact of rituximab desensitization on blood-type-incompatible adult living donor liver transplantation: a Japanese multicenter study.

We evaluated the effects of rituximab prophylaxis on outcomes of ABO-blood-type-incompatible living donor liver transplantation (ABO-I LDLT) in 381 adult patients in the Japanese registry of ABO-I LDLT. Patients underwent dual or triple immunosuppression with or without B cell desensitization therapies such as plasmapheresis, splenectomy, local infusion, intravenous immunoglobulin and rituximab. Era before 2005, intensive care unit-bound status, high Model for End-Stage Liver Disease score and absence of rituximab prophylaxis were significant risk factors for overall survival and antibody-mediated rejection (AMR) in the univariate analysis. After adjustment for era effects in the multivariate analysis, only absence of rituximab prophylaxis was a significant risk factor for AMR, and there were no significant risk factors for survival. Rituximab prophylaxis significantly decreased the incidence of AMR, especially hepatic necrosis (p < 0.001). In the rituximab group, other B cell desensitization therapies had no add-on effects. Multiple or large rituximab doses significantly increased the incidence of infection, and early administration had no advantage. In conclusion, outcomes in adult ABO-I LDLT have significantly improved in the latest era coincident with the introduction of rituximab.

Interferon-γ/CCR5 expression in invariant natural killer T cells and CCL5 expression in capillary veins of dermal papillae correlate with development of psoriasis vulgaris.

BACKGROUND: There have been extensive studies regarding which types of T lymphocytes are involved in psoriasis vulgaris (PV). However, it has remained unclear which types of T lymphocytes might directly contribute to psoriasiform epidermal and vascular hyperplasia. OBJECTIVES: To understand the role of T-cell receptor (TCR)Vα24+ invariant natural killer (iNK)T cells in the development of PV. METHODS: Seventeen patients were enrolled in this study. Using biopsy samples of PV plaques, TCRVα24(+) iNKT cells were investigated regarding their cytokine production to understand their roles in development of disease. RESULTS: The number of interferon (IFN)-γ+ iNKT cells correlated with the length of the psoriasiform hyperplasia rete ridge and the Psoriasis Area and Severity Index. IFN-γ+ iNKT cells in psoriatic skin exhibited higher C-C chemokine receptor (CCR)5 expression, and the amount of C-C chemokine ligand (CCL)5, a ligand for CCR5, was increased in capillary veins of psoriasis plaques. CCR5+ iNKT-cell numbers significantly correlated with the number of capillary vein endothelial cells expressing CCL5 in PV. Furthermore, the number of CCL5+ capillary veins correlated with the maximum rete ridge length. CONCLUSIONS: IFN-γ/CCR5 expression in iNKT cells and CCL5 expression in vessels of dermal papillae correlate with the development of psoriasiform hyperplasia and microabscess. We propose that these iNKT cells may become useful targets for development of novel therapeutic approaches to PV.

Intratesticular and subcutaneous lidocaine alters the intraoperative haemodynamic responses and heart rate variability in male cats undergoing castration.

OBJECTIVE: To evaluate the usefulness of intratesticular and subcutaneous lidocaine in alleviating the intraoperative nociceptive response to castration, measured by pulse rate (PR) and mean arterial pressure (MAP), and to test the applicability of heart rate variability (HRV) analysis in assessing this response. STUDY DESIGN: Randomized, controlled, observer-blinded experimental trial. ANIMALS: Thirty-nine healthy male cats admitted for castration. METHODS: One group received general anaesthesia and served as control group (GA), while the treatment group (LA) additionally received local anaesthesia (lidocaine 2 mg kg(-1)) intratesticularly and subcutaneously. PR and MAP were recorded at anaesthesia baseline (T0), treatment (T1), incision left testicle (T2), traction on spermatic cord (T3), tightening of the autoligature and resection of the cord (T4), incision on the right side (T5), traction on spermatic cord (T6), and tightening of the autoligature and resection of cord (T7). HRV analysis was divided into three 5-minute intervals: baseline (H0), treatment (H1), and surgery (H2). RESULTS: There were significant increases in PR and MAP for both groups during surgery from T3 onwards; however, the increase in the treatment group (LA) was significantly lower than for the control group (GA). For HRV analysis, significant differences were found between groups in the following parameters during surgery: TP (total power), VLF (very low frequency), SDNN (standard deviation of NN intervals [= the interval between two consecutive R-waves in the ECG]), and TI (triangular index), which were lower in the LA group. Mean NN was significantly lower in the GA group, whereas LF (low frequency) and LFn (low frequency, normalized value) were lower in the LA group. HF (high frequency) and HFn (high frequency, normalized value) decreased significantly from H1 to H2 in both groups. CONCLUSIONS AND CLINICAL RELEVANCE: The study showed that the nociceptive response to surgery was alleviated by the use of intratesticular and subcutaneous lidocaine and that HRV analysis is a promising research tool to estimate intraoperative nociception in cats during general anaesthesia.

Protection from non-alcoholic steatohepatitis and liver tumourigenesis in high fat-fed insulin receptor substrate-1-knockout mice despite insulin resistance.

AIMS/HYPOTHESIS: Epidemiological studies have revealed that obesity and diabetes mellitus are independent risk factors for the development of non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma. However, the debate continues on whether insulin resistance as such is directly associated with NASH and liver tumourigenesis. Here, we investigated the incidence of NASH and liver tumourigenesis in Irs1 ( -/- ) mice subjected to a long-term high-fat (HF) diet. Our hypothesis was that hepatic steatosis, rather than insulin resistance may be related to the pathophysiology of these conditions. METHODS: Mice (8 weeks old, C57Bl/6J) were given free access to standard chow (SC) or an HF diet. The development of NASH and liver tumourigenesis was evaluated after mice had been on the above-mentioned diets for 60 weeks. Similarly, Irs1 ( -/- ) mice were also subjected to an HF diet for 60 weeks. RESULTS: Long-term HF diet loading, which causes obesity and insulin resistance, was sufficient to induce NASH and liver tumourigenesis in the C57Bl/6J mice. Obesity and insulin resistance were reduced by switching mice from the HF diet to SC, which also protected these mice against the development of NASH and liver tumourigenesis. However, compared with wild-type mice fed the HF diet, Irs1 ( -/- ) mice fed the HF diet were dramatically protected against NASH and liver tumourigenesis despite the presence of severe insulin resistance and marked postprandial hyperglycaemia. CONCLUSIONS/INTERPRETATION: IRS-1 inhibition might protect against HF diet-induced NASH and liver tumourigenesis, despite the presence of insulin resistance.

Current status of organ transplantation in Japan.

To overcome severe donor shortage, Japanese doctors over the years have developed innovative strategies to maximize organs transplanted per brain death donor and expanded the donor pool using living donors. They also used living and marginal organs and drastically improved living donor lung, liver, pancreas and kidney transplantations. Moreover, they initiated ABO blood type incompatible liver transplantation advancements and succeeded in overcoming the blood type barrier in kidney and liver transplantations. Similar efforts are underway for pancreas transplantation. Furthermore, Japanese doctors have developed a nonaggressive step to achieve immunosuppression following organ transplantation by carefully monitoring donor-specific hyporesponsiveness and infectious immunostatus. However, the institution of amendments to allocation systems and the intensification of efforts to decrease living donor morbidity and to increase the number of brain death donors have remained important issues needing attention. Overall, the strategies Japan has adopted to overcome donor shortage can provide useful insights on how to increase organ transplantations.

Long-term hepatic allograft acceptance based on CD40 blockade by ASKP1240 in nonhuman primates.

Blockade of the CD40-CD154 costimulatory signal is an attractive strategy for immunosuppression and tolerance induction in organ transplantation. Treatment with anti-CD154 monoclonal antibodies (mAbs) results in potent immunosuppression in nonhuman primates (NHPs). Despite plans for future clinical use, further development of these treatments was halted by complications. As an alternative approach, we have been focusing on the inhibition of the counter receptor, CD40 and have shown that a novel human anti-CD40 mAb, ASKP1240, markedly prolongs renal allograft survival in NHPs, although allografts eventually underwent chronic allograft nephropathy. On the basis of our previous findings that a CD40-CD154 costimulation blockade induces tolerance to hepatic, but not cardiac, allografts in rodents, we tested here our hypothesis that a blockade of CD40 by ASKP1240 allows acceptance of hepatic allografts in NHPs. A 2-week ASKP1240 induction treatment prolonged liver allograft survival in NHPs; however, the graft function deteriorated due to chronic rejection. In contrast, a 6-month ASKP1240 maintenance monotherapy efficiently suppressed both cellular and humoral alloimmune responses and prevented rejection on the hepatic allograft. No serious side effects, including thromboembolic complications, were noted in the ASKP1240-treated monkeys. We conclude that CD40 blockade by ASKP1240 would be a desirable immunosuppressant for clinical liver transplantation.

Effect of maintenance therapy with low-dose peginterferon for recurrent hepatitis C after living donor liver transplantation.

Approximately 30% of patients who have recurrent hepatitis C after liver transplantation achieve sustained virological response (SVR) by taking a combination therapy of pegylated interferon and ribavirin. For the remaining non-SVR patients, an effective management treatment has not yet been established. In this study, efficacy of long-term peginterferon maintenance therapy for non-SVR patients was evaluated. Forty patients who had previously received the combination therapy for hepatitis C after living donor liver transplantation were classified into one of the following three groups: the SVR group (n = 11); the non-SVR-IFN group (n =17), which received low-dose peginterferon maintenance therapy for non-SVR patients; and the non-SVR-Withdrawal group (n = 12), which discontinued the interferon treatment. We then compared histological changes among these three groups after 2 or more years follow-up. Activity grade of liver histology improved or remained stable in patients in the SVR and non-SVR-IFN groups, but deteriorated in half of the patients in the non-SVR-Withdrawal group. Fibrosis improved or remained stable in 10 of 11 SVR patients and in 13 of 17 non-SVR-IFN patients, but deteriorated in all non-SVR-Withdrawal patients. Mean changes in fibrosis stage between pretreatment and final liver biopsy were -0.18, +0.06 and +2.2 in the SVR, non-SVR-IFN and non-SVR-Withdrawal groups, respectively. Fibrosis stage deteriorated to F3 or F4 significantly more rapidly in the non-SVR-Withdrawal group than in the other two groups. In conclusion, continuing long-term maintenance therapy with peginterferon prevented histological progression of hepatitis C in patients who had undergone living donor liver transplantation.

The challenge of acute rejection in intestinal transplantation.

Early diagnosis and treatment of acute cellular rejection (ACR) after intestinal transplantation (ITx) is challenging. We report the outcome of three patients: two presented mild ACR improved with steroids. One presented steroid-resistant severe rejection, improved after rabbit anti-thymocyte globulin (r-ATG), but unfortunately died for encephalitis caused by opportunistic infections.

Enantioselective pharmacokinetics of ketoprofen in piglets: the significance of neonatal age.

Following intravenous dose of 6mg/kg racemic ketoprofen, the chiral pharmacokinetics of ketoprofen was investigated in eight piglets aged 6 and 21days old. S-ketoprofen predominated over R-ketoprofen in plasma of the piglets in both age groups. The volumes of distribution of S-ketoprofen for the 6- and 21-day-old piglets were 241.7 (211.3-276.5) mL/kg and 155.0 (138.7-173.1) mL/kg, respectively, while the corresponding parameters for R-ketoprofen were 289.2 (250.3-334.2) mL/kg and 193.0 (168.7-220.8) mL/kg. The clearances of R-ketoprofen [948.4 (768.0-1171.2) mL/h/kg and 425 (319.1-566.0) mL/h/kg for the 6- and 21-day-old piglets, respectively] were significantly higher compared to the clearances of S-ketoprofen [57.3 (46.6-70.4) mL/h/kg and 33.8 (27.0-42.2) mL/h/kg for 6- and 21-day-old piglets, respectively]. The elimination half-life of S-ketoprofen was 3.4h for both age groups, while the elimination half-life of R-ketoprofen was 0.2h for the 6-day-old and 0.4h for the 21-day-old piglets. The clearances of both R- and S-ketoprofen were significantly higher in the 6-day-old piglets compared to when they were 21 days old. Furthermore, the volumes of distribution were larger in the youngest age group.

Pharmacokinetics and pharmacodynamic effects of meloxicam in piglets subjected to a kaolin inflammation model.

The pharmacokinetics and the analgesic, anti-inflammatory and antipyretic effects of meloxicam were investigated in a placebo controlled study in 2-week-old piglets. Inflammation was induced by a subcutaneous injection of kaolin in the left metacarpus, and 16 h later, meloxicam (0.6 mg/kg) or saline was administered intramuscularly. The absorption half-life was relatively short (0.19 h) and the elimination half-life was 2.6 h. Mechanical nociceptive threshold testing was used to evaluate the analgesic effect, but no significant effect of the meloxicam treatment was found. The skin temperature of the inflamed area increased after the kaolin injection, but no significant decrease in temperature was found after administration of meloxicam. Only limited pyresis was observed after the kaolin injection, and no significant antipyretic effect of meloxicam was found. The results indicated that this dose of meloxicam had very limited anti-inflammatory and analgesic effects in piglets.

Ketoprofen in piglets: enantioselective pharmacokinetics, pharmacodynamics and PK/PD modelling.

The chiral pharmacokinetics and pharmacodynamics of ketoprofen were investigated in a placebo-controlled study in piglets after intramuscular administration of 6 mg/kg racemic ketoprofen. The absorption half-lives of both enantiomers were short, and S-ketoprofen predominated over R-ketoprofen in plasma. A kaolin-induced inflammation model was used to evaluate the anti-inflammatory, antipyretic and analgesic effects of ketoprofen. Skin temperatures increased after the kaolin injection, but the effect of ketoprofen was small. No significant antipyretic effects could be detected, but body temperatures tended to be lower in the ketoprofen-treated piglets. Mechanical nociceptive threshold testing was used to evaluate the analgesic effects. The piglets in the ketoprofen-treated group had significantly higher mechanical nociceptive thresholds compared to the piglets in the placebo group for 12-24 h following the treatment. Pharmacokinetic/pharmacodynamic modelling of the results from the mechanical nociceptive threshold testing gave a median IC(50) for S-ketoprofen of 26.7 µg/mL and an IC(50) for R-ketoprofen of 1.6 µg/mL. This indicates that R-ketoprofen is a more potent analgesic than S-ketoprofen in piglets. Estimated ED(50) for racemic ketoprofen was 2.5 mg/kg.

Clinical features of biochemical cholestasis in patients with recurrent hepatitis C after living-donor liver transplantation.

Recurrent hepatitis C after liver transplantation (HepC-LT) progresses faster than hepatitis C in non-transplant settings. Cholestasis has been suggested to be one characteristic of HepC-LT related to the rapid progression. We investigated the clinical features of biochemical cholestasis, which we defined as high serum concentrations of alkaline phosphatase and gamma-glutamyl transpeptidase, in patients with recurrent hepatitis C after living-donor liver transplantation. Eighty patients were diagnosed with post-transplant recurrent hepatitis C after exclusion of other aetiologies of cholestasis by liver biopsy and imaging. The clinical features of biochemical cholestasis in the patients with HepC-LT, including histological changes, the efficacy of interferon therapy and helper T-cell (Th) subsets in the peripheral blood, were analysed. Fifty-five of the 80 patients with HepC-LT (69%) had evidence of biochemical cholestasis. Progression of liver fibrosis to stage F3 or F4 was significantly accelerated in patients with biochemical cholestasis compared with patients without cholestasis. The biochemical cholestasis in patients with HepC-LT improved after interferon therapy in 22 of 39 patients (56%) who showed a virological response to the therapy, suggesting that hepatitis C virus (HCV) caused the biochemical cholestasis in these patients. Patients with biochemical cholestasis who had a biochemical response to interferon therapy showed an increased Th1 responses in peripheral blood. In conclusion, biochemical cholestasis is the characteristic feature of HepC-LT and is related to progression of liver fibrosis. An increased Th1 response is associated with cholestasis caused by HCV after liver transplantation.

IgA rheumatoid factor in primary Sjogren's syndrome.

OBJECTIVE: To assess the serum level of immunoglobulin A rheumatoid factor (IgA-RF) in patients with primary Sjogren's syndrome (pSS) and study the association with immunological and clinical factors. METHODS: Sera from 97 pSS patients diagnosed according to the preliminary European criteria and 100 controls were analysed for IgA-RF in a cross-sectional study design. RESULTS: IgA-RF was detected in serum of 25.8% of the pSS patients and in 1% of the controls. In patients with positive vs. negative IgA-RF, the focus scores in biopsy of the minor salivary glands were 4.41 and 1.43 (p<0.0001), respectively. There was a correlation between positive IgA-RF and positive antinuclear antibodies (ANA) (r = 0.263, p<0.009), IgM-RF (r = 0.70, p<0.0001), anti-SSA/SSB (r = 0.73, p<0.0001), and a high serum level of IgG (r = 0.59, p<0.0001). The presence of renal disease was higher in IgA-RF-positive vs. negative pSS patients (20.0% vs. 5.6%, p = 0.047). The serum level of the hormone prolactin (PRL) correlated to the serum level of IgA-RF (r = 0.31, p = 0.026). CONCLUSIONS: The presence of IgA-RF in patients with pSS is closely associated with the presence of autoantibodies, and with focus scoring in biopsies of the salivary glands. IgA-RF is associated with renal disease in pSS but we found no correlation to other extraglandular manifestations.

Portal vein complications in pediatric living donor liver transplantation using left-side grafts.

The aim of this report is to assess the rate of portal vein complications (PVCs), the success rate of treatment for PVCs and the prognosis of patients with PVCs for pediatric living donor liver transplantation (LDLT). Pre- and postoperative records of 521 pediatric LDLTs, using left-side grafts were retrospectively reviewed. The overall rate of PVC was 9%, with early PVC occurring in nine patients (1.7%) with a mortality rate of 67% and late PVC in 38 patients (7.3%). Fifteen of these patients with late PVC showed complete portal vein occlusion despite various treatments, and in six of them the graft was lost. Histological examination revealed fibrosis in portal areas in 13 patients, around the central veins associated with cholestasis in the parenchyma in 10, and hepatocyte ballooning in 12. Correction of portal vein flow or retransplantation is necessary for the rescue of patients with early PVCs. Graft loss in the long term may be high with the occurrence of liver failure or portal hypertension related causes, such as hepatopulmonary syndrome and gastrointestinal bleeding in patients with late PVCs. For the rescue of these patients, especially for patients with body weight < 6 kg, regular monitoring of portal vein flow is essential.

Differential alterations in expressions of ryanodine receptor subtypes in cerebellar cortical neurons of an ataxic mutant, rolling mouse Nagoya.

This study aimed to clarify changes in the spatial expressions of types 1, 2 and 3 ryanodine receptors (RyR1, RyR2 and RyR3) in the cerebellum of a Ca(2+) channel alpha(1A) subunit mutant, rolling mouse Nagoya. Semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) revealed that the mRNA signal levels of RyR1 and RyR3 were altered in the rolling cerebellum, which exhibited lower densities of RyR1 bands and higher densities of RyR3 bands than in the control cerebellum. Quite consistent with the RT-PCR results, the staining intensity of RyR1 and RyR3 was altered in the rolling cerebellum. RyR1 immunostaining appeared in somata and the proximal dendrites of Purkinje cells, and the staining intensity of both subcellular regions was equally lower in all cerebellar lobules of rolling mice than in those of controls. Although RyR3 immunostaining appeared in the dendrites of granule cells, more intense RyR3 staining in rolling mice than in controls was uniformly observed throughout all cerebellar lobules. The present study further examined co-localizations of ryanodine receptor subtypes and voltage-gated Ca(2+) channel alpha(1) subunits in the rolling cerebellum. Somatodendritic RyR1 immunostaining in Purkinje cells overlapped with either a mutated Ca(2+) channel alpha(1A) subunit (P/Q-type), or a Ca(2+) channel alpha(1C) subunit (L-type; dihydropyridine receptor) immunostaining. Immunostaining of these alpha(1) subunits also emerged in granule cells. Those results suggest non-region-related alterations in RyR1 and RyR3 expressions in the rolling mouse cerebellum. Such expressional changes in ryanodine receptor subtypes may be involved in Ca(2+) channel alpha(1A) subunit gene mutation, and may alter regulation of intracellular Ca(2+) concentrations in cerebellar cortical neurons.

Voided stain on paper method for analysis of mouse urination.

AIMS: To evaluate the usefulness of a quantification method using filter paper for analyzing minute voided urine of the mouse. METHODS: Voided stain on paper (VSOP) method; the correlation between area of stained spot on a filter paper and amount of applied liquid was calculated. Voiding behavior of the mice was analyzed by placing the animal above the same filter paper and recording voided time and area over 2 hr. The usefulness of the VSOP method was tested in analysis of the voiding behavior of five female 7-week-old ddY mice treated with cyclophosphamide (CPM, 150 mg/kg, intraperitoneally) and five control ones, in comparison with the histology of CPM-induced cystitis. Further, the voided volume of male and female ddY mouse ranging from 2 to 13 weeks was assessed. RESULTS: There was a linear correlation between liquid volume and stained area on the filter paper (y = 16.472x - 22.411, R(2) = 0.9981). Between control mice and those with histologically proven CPM cystitis, there was a significant difference in voided volume (362.7 +/- 51.9 and 127.8 +/- 100.0 microl, < 0.001) and voiding interval (10.30 +/- 3.10 and 4.47 +/- 1.70 min, < 0.001). Voided volume of ddY mice was quantifiable from as early as 2-week old, increased along with their growth and correlated well with their body weight [(voided volume: microl) = 10.8 x (body weight: g) + 32, R(2) = 0.762]. CONCLUSIONS: The VSOP method is a useful tool for evaluating voiding behavior of the mouse, including those with small bladder capacity.

Pharmacokinetics and pharmacodynamics of meloxicam in piglets.

The pharmacokinetics and pharmacodynamics of meloxicam in piglets (16-23 days old) were studied using a stratified parallel group design. One group (n = 13) received 0.4 mg/kg meloxicam intravenously, while the other group (n = 12) received physiological saline solution. A carrageenan-sponge model of acute inflammation was used to evaluate the effects of meloxicam. The plasma clearance was low (0.061 L/kg/h), the volume of distribution was low (0.19 L/kg) and the elimination half-life was short (2.7 h). At most time points, the mean concentration of meloxicam in plasma exceeded the concentrations in exudate indicating a limited accumulation of the drug at the site of the inflammation. There were significant differences between the groups in the exudate prostaglandin E2 (PGE2) concentration, but the inhibition of PGE2 in the meloxicam group was limited. The inhibition of thromboxane B(2) (TXB2) production in serum in the meloxicam group was extensive, but of shorter duration than the PGE2 inhibition in exudate.