A scalable hyperthermic intravesical chemotherapy (HIVEC) setup for rat models of bladder cancer.

Hyperthermic intravesical chemotherapy (HIVEC)-whereby the bladder is heated to ± 43 °C during a chemotherapy instillation-can improve outcomes of non-muscle invasive bladder cancer (NMIBC) treatments. Experiments in animal models are required to explore new hyperthermia based treatments. Existing HIVEC devices are not suitable for rodents or large-scale animal trials. We present a HIVEC setup compatible with orthotopic rat models. An externally heated chemotherapeutic solution is circulated in the bladder through a double-lumen catheter with flow rates controlled using a peristaltic pump. Temperature sensors in the inflow channel, bladder and outflow channel allow temperature monitoring and adjustments in real-time. At a constant flow rate of 2.5 mL/min the system rapidly reaches the desired bladder temperature of 42-43 °C with minimal variability throughout a one-hour treatment in a rat bladder phantom, as well as in euthanised and live rats. Mean intraluminal bladder temperatures were 42.92 °C (SD = 0.15 °C), 42.45 °C (SD = 0.37 °C) and 42.52 °C (SD = 0.09 °C) in the bladder phantom, euthanised, and live rats respectively. Thermal camera measurements showed homogenous heat distributions over the bladder wall. The setup provides well-controlled thermal dose and the upscaling needed for performing large scale HIVEC experiments in rats.

The Netherlands Sports Cardiology Map: a step towards sports cardiology network medicine for patient and athlete care.

Sports cardiology is a rapidly evolving subspecialty of cardiology, with a growing demand for expertise. To improve patient care, clinicians, patients, and athletes (recreational to elite) should be able to easily identify specialised care pathways, expertise centres and clinicians with sports cardiology expertise. To this purpose, several international societies and organisations recommend establishing a local and national sports cardiology infrastructure. We therefore aimed to establish The Netherlands Sports Cardiology Map. We conducted a web-based survey, which was published on the Netherlands Society of Cardiology home page (2019-2020) and in which each cardiology department or clinic was asked to provide information on sports cardiology expertise and the current infrastructure. Of the 46 respondent centres, 28 (61%) reported that they had expertise in sports cardiology, of which 22 (79%) had specific expertise in one or more specific types of sports. Integrated multidisciplinary meetings were reported by 43% of the centres (n = 12/28). Only two centres reported ongoing research projects that had been approved by an institutional review board. The Netherlands Sports Cardiology Map is an important step towards improving the existing infrastructure and developing network medicine for sports cardiology.

Safety and immunogenicity profile of an experimental hepatitis B vaccine adjuvanted with AS04.

The reactogenicity and safety of an experimental hepatitis B (HB) vaccine containing adjuvant system (AS04) was compared with a licensed vaccine in a phase III, single-blind, randomised study in healthy volunteers >or=15 years of age. A total of 1303 subjects were enrolled to receive either two doses of HB-AS04 (0, 6 months) or three doses of the comparator vaccine (0, 1, 6 months). Two doses of HB-AS04 elicited seroprotection rates close to 100% and two-fold higher GMTs than the comparator vaccine. Results showed that both vaccines were well tolerated and the general safety profile of HB-AS04 was similar to that of the comparator vaccine.

Vitamin K deficiency and bleeding after long-term use of cholestyramine.

Although it has been long known that in theory the use of cholestyramine can cause coagulopathy due to reduced absorption of vitamin K, only a few cases have been reported. In those cases the coagulopathy occurred within a few weeks to months after the start of therapy. We report a patient with severe pruritus due to intrahepatic cholestasis, who was on cholestyramine therapy for over 25 years before haemorrhage occurred. This case demonstrates that one should be aware of the possibility of depletion of fat-soluble vitamins during the long-term use of cholestyramine.

[From gene to disease; Wilson disease: copper storage due to mutations in ATP7B]. / Van gen naar ziekte; de ziekte van Wilson: koperstapeling door mutaties in ATP7B.

Wilson disease is an autosomal recessive disorder of copper metabolism. The gene defective in Wilson disease encodes a copper transporting P-type ATPase expressed in the liver. The disturbed export of copper into bile results in accumulation of copper in liver and secondarily in other organs such as the brain. These patients generally present with either hepatic or neurological symptoms.

Health strategy on HCV in The Netherlands.

The current basis for the health care policy on hepatitis C in The Netherlands is an advisory report of the national Health Council, published in 1997. The Council confirmed that: Chronic hepatitis C (HC) is to be considered as a serious disease; the hepatitis C virus (HCV) can be detected easily and accurately; transmission of HCV occurs mainly via blood; the prevalence of HC is low in The Netherlands and comparable to or somewhat lower than other countries in Northern Europe; treatment is possible and worthwhile; patients have the right to be provided spontaneously with relevant information; the general population lacks adequate knowledge about the essentials of HCV infection, preventing them from taking adequate measures for their own health. The Council recommended that: general tracing and testing of all people who received blood products in the past would be inefficient; hospitals should keep precise records of the origin and use of blood products; as practically all active drug users in The Netherlands are involved in medical care in connection with their addiction, they will be tested for HCV and qualify for treatment of HC; information should be provided to the general population; medical doctors are stimulated to participate in training courses on HC; medical and non-medical professionals involved in increased risk of HCV transmission must be informed on hygiene. Epidemiological research of HCV infection in the various population groups of The Netherlands is stimulated. Currently, an active approach to the health care policy on hepatitis C is supported by the Ministry of Health, Welfare and Sport, including awareness programs in risk groups and training courses for professionals. Such programs are typically aiming at supporting and stimulating the own initiatives in the society, based on responsibilities of professional and patient's organisations and individuals at risk. Treatment of HC, given in accordance with the current consensus, including long term combination therapy with interferon and ribavirin, is available and refundable for all Dutch citizens. A special program for HC screening and treatment of drug addicts is being started up, using the special infrastructure for drug user control programs in The Netherlands.

Characterization of a human monoclonal antibody obtained after immunization with plasma vaccine and a booster with recombinant-DNA hepatitis B vaccine.

A human monoclonal antibody type IgG4, designated 1Ff4, was obtained by Epstein Barr virus transformation of peripheral blood lymphocytes from a hepatitis B vaccinee (HB-VAX: plasma-derived vaccine) after one boost of yeast recombinant DNA derived vaccine (Engerix-B). 1Ff4 binds preferentially to HBsAg/adw(2) and HBsAg/ayw(1). In binding experiments, it competes with antibodies induced by vaccination with HB-VAX-DNA (yeast recombinant) and HB-VAX (plasma-derived vaccine). 1Ff4 competes in part with a monoclonal antibody for the w/r region. Partial inhibition of binding of HBsAg/adw(2) to solid phase anti-HBs was detected, resembling inhibition obtained using other human monoclonal specific for the "a"-loop. 1Ff4 does not bind to linear peptides covering the two "a"-loops or to an adw(2)/G145R mutant, its binding to wild type HBsAg strongly depends on the presence of disulphide bonds. In a large series of HBsAg-positive samples from an endemic area, 1Ff4 antibodies were successfully used to discriminate between an adw(2) and an adrq+ strain. The characterisation of 1Ff4 and other human monoclonal anti-HBs antibodies may help to understand the fine specificity of protective antibodies elicited by immunization.

Influence of ultraviolet B exposure on immune responses following hepatitis B vaccination in human volunteers.

Exposure to ultraviolet radiation can modulate immune responses in animal and humans. Remarkably, the ultraviolet-induced immunosuppression is not restricted to the exposed skin but is also found at other body sites, i.e., systemic immunosuppression. Effects of ultraviolet radiation on infections cannot be determined by experimentation on humans, but the effects of ultraviolet on vaccination may serve as a model. Moreover, it is important in its own right to assess whether ultraviolet radiation affects vaccination responses. In this study the effect of ultraviolet B exposure on the development of immune responses after hepatitis B vaccination in human volunteers was investigated. To this end, 191 human volunteers were vaccinated against hepatitis B with the Engerix-B vaccine. Ninety-seven of them were prior to the first vaccination exposed to ultraviolet B on 5 consecutive days with one personal minimal erythema dose per day. At several time-points before and after the ultraviolet B exposure regimen and the vaccination, blood samples were taken. Parameters for specific as well as nonspecific cellular and humoral immunity were analyzed. It was demonstrated that ultraviolet B exposure prior to hepatitis B vaccination did not alter the cellular (lymphocyte stimulation test) nor the humoral (antibody titers) immune response against hepatitis B surface antigen significantly. In contrast, contact hypersensitivity to diphenylcyclopropenone was significantly suppressed after ultraviolet B exposure, as was natural killer cell activity. These latter results confirm earlier findings and demonstrate immunosuppressive effectiveness of the ultraviolet regimen. In summary, although natural killer cell activity and contact hypersensitivity responses were suppressed, the ultraviolet B radiation protocol did not alter the humoral nor the cellular immune responses against hepatitis B surface antigen after vaccination.

Extrahepatic portal vein thrombosis: aetiology and determinants of survival.

BACKGROUND: Malignancy, hypercoagulability, and conditions leading to decreased portal flow have been reported to contribute to the aetiology of extrahepatic portal vein thrombosis (EPVT). Mortality of patients with EPVT may be associated with these concurrent medical conditions or with manifestations of portal hypertension, such as variceal haemorrhage. PATIENTS AND METHODS: To determine which variables have prognostic significance with respect to survival, we performed a retrospective study of 172 adult EPVT patients who were followed over the period 1984-1997 in eight university hospitals. RESULTS: Mean follow up was 3.9 years (range 0.1-13.1). Overall survival was 70% (95% confidence interval (CI) 62-76%) at one year, 61% (95% CI, 52-67%) at five years, and 54% (95% CI, 45-62%) at 10 years. The one, five, and 10 year survival rates in the absence of cancer, cirrhosis, and mesenteric vein thrombosis were 95% (95% CI 87-98%), 89% (95% CI 78-94%), and 81% (95% CI 67-89%), respectively (n=83). Variables at diagnosis associated with reduced survival according to multivariate analysis were advanced age, malignancy, cirrhosis, mesenteric vein thrombosis, absence of abdominal inflammation, and serum levels of aminotransferase and albumin. The presence of variceal haemorrhage and myeloproliferative disorders did not influence survival. Only four patients died due to variceal haemorrhage and one due to complications of a portosystemic shunt procedure. CONCLUSION: We conclude that mortality among patients with EPVT is related primarily to concurrent disorders leading to EPVT and not to complications of portal hypertension.

An open study of subcutaneous administration of inactivated hepatitis A vaccine (VAQTA) in adults: safety, tolerability, and immunogenicity.

A number of patients in clinical practice would be candidates for hepatitis A vaccine administered subcutaneously (SC), including patients with inherited and acquired coagulopathies. To assess the safety, tolerability, and immunogenicity of VAQTA (Hepatitis A Vaccine, Inactivated, Merck and Co. Inc., West Point, PA) was administered SC to healthy adults. A total of 114 healthy adults received two doses of vaccine SC 24 weeks apart. No serious vaccine-related adverse experiences were reported. Four weeks after dose 1, the seropositivity rate (SPR) was 77.9% (CI, 69.1, 85.1%). The geometric mean titer (GMT) was 21.0 mIU/ml. Twenty-four weeks after dose 1 (just prior to dose 2) and 28 weeks after dose 1 (4 weeks following dose 2), the SPRs were 95.3% [corrected] and 100%, respectively; the GMTs were 153.2 and 1563.9 mIU/mL, respectively [corrected]. Although the kinetics of the immune response were slower when VAQTA was administered SC compared to intramuscular injection, SPRs and GMTs increased over time, indicating that the vaccine administered SC demonstrated immunogenicity.

Treatment of chronic hepatitis C: lessons from human immunodeficiency virus dynamics.

Treatment of chronic hepatitis C is a major problem. A sustained viral response to interferon alpha monotherapy occurs in <20% of patients. Using a combination therapy of interferon alpha and ribavirin. the sustained response rate in naive hepatitis C patients has increased to 31%-47%. The success of therapy for chronic hepatitis C depends on both virus- and host-related factors, such as age, histology, duration of hepatitis C virus (HCV) carriage and biochemical parameters. During the last 5 years, insight into the dynamics of human immunodeficency virus (HIV) has been obtained by analysing the changes in viral load after starting antiviral treatment. By using a mathematical model of HIV kinetics as an example, an exponentially rapid decline in serum HCV RNA level was seen after the first dose of interferon alpha, followed by a slower exponential decline: a so-called biphasic pattern. The estimated virion half-life varies between 2.7 and 16.8 h. The high virion turnover allows the generation of a heterogeneous quasi-species population of HCVs. It is therefore supposed that initial aggressive treatment can be helpful to prevent the development of mutations that make the virus more defensible for the interferon alpha treatment. Various trials are now being conducted based on this principle of high induction antiviral therapy.

Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study.

In a collaborative multicenter case-control study, we investigated the effect of factor V Leiden mutation, prothrombin gene mutation, and inherited deficiencies of protein C, protein S, and antithrombin on the risk of Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT). We compared 43 BCS patients and 92 PVT patients with 474 population-based controls. The relative risk of BCS was 11.3 (95% CI 4.8-26.5) for individuals with factor V Leiden mutation, 2.1(95% CI 0.4-9.6) for those with prothrombin gene mutation, and 6.8 (95% CI 1.9-24.4) for those with protein C deficiency. The relative risk of PVT was 2.7 (95% CI 1.1-6.9) for individuals with factor V Leiden mutation, 1.4 (95% CI 0.4-5.2) for those with prothrombin gene mutation, and 4.6 (95% CI 1.5-14.1) for those with protein C deficiency. The relative risk of BCS or PVT was not increased in the presence of inherited protein S or antithrombin deficiency. Concurrence of either acquired or inherited thrombotic risk factors was observed in 26% of the BCS patients and 37% of the PVT patients. We conclude that factor V Leiden mutation and hereditary protein C deficiency appear to be important risk factors for BCS and PVT. Although the prevalence of the prothrombin gene mutation was increased, it was not found to be a significant risk factor for BCS and PVT. The coexistence of thrombogenic risk factors in many patients indicates that BCS and PVT can be the result of a combined effect of different pathogenetic mechanisms.

A survey of liver pathology in needle biopsies from HBsAg and anti-HBe positive individuals.

AIMS: To use laboratory data and liver biopsies, prospectively obtained from hepatitis B surface antigen (HBsAg) and anti hepatitis B e antigen (anti-HBe) positive patients, for the assessment of: (1) the relation between biopsy length/number of portal tracts and sampling error; (2) the relation between the severity of piecemeal necrosis and the new grading terminology (minimal, mild, moderate, and severe chronic hepatitis); and (3) liver pathology, which has not been studied in patients with this specific serological profile. METHODS: The study group (n = 174) included 104 patients with normal aminotransferase concentrations and no cases with clinically apparent cirrhosis. The specimen length and number of portal tracts were measured at light microscopy examination. Sampling error analysis was related to the discrepancies between aminotransferase concentrations versus histological grade. Detailed histological scorings were undertaken by the reference pathologist and compared with laboratory and hepatitis B virus (HBV) DNA precore sequence data. RESULTS: Sampling error seemed to be a constant feature, even for biopsies > or = 20 mm, but increased dramatically in biopsies < 5 mm long and/or containing less than four portal tracts. Between 25% and 30% of biopsies, graded as "mild" or "moderate" activity showed features of moderate and severe piecemeal necrosis, respectively. Ten per cent of the patients with normal aminotransferase values had stage III-IV hepatic fibrosis, and 20% had piecemeal necrosis. Only cytoplasmic, not nuclear, core antigen expression was a strong predictor of high hepatitis B viraemia. There was no association between precore stop codon mutations, grade/stage of liver disease, and hepatitis B core antigen (HBcAg) expression. CONCLUSIONS: The specimen available for light microscopical examination should be > 5 mm long and should contain more than four portal tracts. In addition, the new grading terminology might give the clinician an inappropriately mild impression of the severity of piecemeal necrosis. Furthermore, even in the presence of normal aminotransferase concentrations, considerable liver pathology can be found in 10-20% of HBsAg and anti-HBe positive individuals; such pathology is not associated with the occurrence of precore stop codon mutations.

Budesonide or prednisone in combination with ursodeoxycholic acid in primary sclerosing cholangitis: a randomized double-blind pilot study. Belgian-Dutch PSC Study Group.

OBJECTIVE: PSC has characteristics of an (auto)immune-mediated disease: however, few studies have evaluated corticosteroid therapy for this disorder. METHODS: We performed an 8-wk double-blind randomized pilot study to assess the effects of additional treatment with 9 mg budesonide (n = 6) versus 3 mg budesonide (n = 6) versus 10 mg prednisone (n = 6) in patients who had been treated with UDCA (mean dose, 12 mg/kg/day) for at least 5 months without achieving biochemical remission. Pruritus and fatigue were evaluated using visual analog scales. Serum liver biochemistry was measured every 4 wk. At entry and at the end of the trial, adrenocorticotrophic hormone (ACTH) and dehydroepiandrosterone (DHEA) were measured to assess effects on the pituitary-adrenal axis. Duodenal bile was collected for assessment of biliary corticosteroid activity. RESULTS: Pruritus decreased significantly more in the prednisone group compared to both the 3-mg and the 9-mg budesonide groups (p < 0.05). Alkaline phosphatase (mean: -23.4%; p = 0.03) and IgG (mean: -16.2%; p = 0.04) decreased in the prednisone group, whereas bilirubin, gamma-glutamyl transferase, aspartate aminotransferase, and alanine aminotransferase did not change significantly. No significant clinical or liver biochemical changes were observed in the 3-mg and 9-mg budesonide groups. Significantly larger drops in serum ACTH were found in the 10-mg prednisone group (-40.7%; p = 0.04) and 9-mg budesonide group (-36.6%; p = 0.02) compared to the 3-mg budesonide group (+ 19.0%). No significant differences in percentage change in baseline values for DHEA between the three treatment arms were found. Mononuclear cell proliferation assays did not demonstrate corticosteroid activity in bile. Autoimmune hepatitis was observed in one case (9 mg budesonide) when corticosteroids were tapered off. CONCLUSION: The results of this pilot study suggest only minor beneficial short-term effects of prednisone but not budesonide on symptoms and serum liver tests in UDCA-treated PSC patients.

Congenital hepatic fibrosis in 3 siblings with phosphomannose isomerase deficiency.

Congenital hepatic fibrosis is a rare disorder of intrahepatic bile ducts with the persistence of embryological bile duct structures in ductal plate configuration. Three siblings aged 18, 17 and 14 years old were found to have congenital hepatic fibrosis associated with a deficiency of the enzyme phosphomannose isomerase. The clinical symptoms were recurrent attacks of persistent vomiting with diarrhea and mild hepatomegaly. The biochemical abnormalities included elevated serum transferases during attacks, clotting factor deficiencies and persistent hypoalbuminemia. In the youngest patient protein-losing enteropathy was present. Liver biopsies of the three patients taken when they were 1, 3 and 14 years old showed an excess of bile duct structures in ductal plate configuration with mild fibrosis in the portal triads. In one patient the liver biopsy was repeated after 18 years and showed only a mild progression of fibrosis in the portal triads. Duodenal biopsies taken in infancy in two of the three patients did not show any abnormalities. Recognition of phosphomannose isomerase deficiency in association with congenital hepatic fibrosis and protein-losing enteropathy is important, because some of the clinical symptoms are potentially treatable by oral mannose therapy.

FcalphaRI-positive liver Kupffer cells: reappraisal of the function of immunoglobulin A in immunity.

Despite the well-recognized involvement of immunoglobulin (Ig) A in mucosal immunity, the function of its receptor, FcalphaRI (CD89), is poorly understood. The ability of FcalphaRI to activate leukocytes seems to conflict with the proposed anti-inflammatory activity of secretory IgA. We show here that in a transgenic mouse model, inflammatory mediators induced expression of FcalphaRI on Kupffer cells, which enabled efficient phagocytosis in vivo of bacteria coated with serum IgA. Secretory IgA did not initiate phagocytosis. Therefore, interactions between serum IgA and FcalphaRI on Kupffer cells may provide a 'second line of defense' in mucosal immunity, by eliminating invasive bacteria entering through the portal circulation and thus preventing disease.

Interference of antibody production to hepatitis B surface antigen in a combination hepatitis A/hepatitis B vaccine.

A randomized trial comparing 3 manufacturing consistency lots of a combination hepatitis A/hepatitis B vaccine to each other and to hepatitis A vaccine and hepatitis B vaccine given separately and concurrently was done to evaluate safety, tolerability, and immunogenicity. Healthy volunteers >/=11 years of age were divided into 4 groups. Each of 3 groups received a separate consistency lot of the combination vaccine, and 1 group received separate but concurrent injections of hepatitis A and hepatitis B vaccines. Injections were given at weeks 0 and 24. The combination vaccine was generally well tolerated. The hepatitis A portion of the combination vaccine produced clinically acceptable high seropositivity rates 4 and 52 weeks after the first injection. The hepatitis B portion of the vaccine did not produce clinically acceptable seropositivity rates 4 weeks after the second injection. Lack of antibody production may be attributed, at least in part, to immunologic interference.