Proton pump inhibitors protect mice from acute systemic inflammation and induce long-term cross-tolerance.

Incidence of sepsis is increasing, representing a tremendous burden for health-care systems. Death in acute sepsis is attributed to hyperinflammatory responses, but the underlying mechanisms are still unclear. We report here that proton pump inhibitors (PPIs), which block gastric acid secretion, selectively inhibited tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) secretion by Toll-like receptor (TLR)-activated human monocytes in vitro, in the absence of toxic effects. Remarkably, the oversecretion of IL-1ß that represents a hallmark of monocytes from patients affected by cryopyrin-associated periodic syndrome is also blocked. Based on these propaedeutic experiments, we tested the effects of high doses of PPIs in vivo in the mouse model of endotoxic shock. Our data show that a single administration of PPI protected mice from death (60% survival versus 5% of untreated mice) and decreased TNF-α and IL-1ß systemic production. PPIs were efficacious even when administered after lipopolysaccharide (LPS) injection. PPI-treated mice that survived developed a long-term cross-tolerance, becoming resistant to LPS- and zymosan-induced sepsis. In vitro, their macrophages displayed impaired TNF-α and IL-1ß to different TLR ligands. PPIs also prevented sodium thioglycollate-induced peritoneal inflammation, indicating their efficacy also in a non-infectious setting independent of TLR stimulation. Lack of toxicity and therapeutic effectiveness make PPIs promising new drugs against sepsis and other severe inflammatory conditions.

[Current perspectives on supportive care for lung cancer patients]. / Perspectives actuelles sur les soins de support aux patients atteints d'un cancer du poumon.

The fight against cancer comprises not only survival of the disease but also survival with the highest possible quality of life. Thus, supportive care in cancer aims at reducing physical and psycho-emotional symptom burden. Furthermore, supportive care in cancer includes self-management-support for patients and their families/caregivers. Due to high symptom prevalence and poor prognosis, lung cancer patients express more unmet supportive care needs than other patient populations with cancer. Interventions to meet these needs have been developed in the last decade. They involve new models of care that incorporate the role of a lung cancer nurse in comprehensive cancer centers and eHealth-systems to support lung cancer patients and their families/caregivers.

The role of advanced nursing in lung cancer: A framework based development.

PURPOSE: Advanced Practice Lung Cancer Nurses (APLCN) are well-established in several countries but their role has yet to be established in Switzerland. Developing an innovative nursing role requires a structured approach to guide successful implementation and to meet the overarching goal of improved nursing sensitive patient outcomes. The "Participatory, Evidence-based, Patient-focused process, for guiding the development, implementation, and evaluation of advanced practice nursing" (PEPPA framework) is one approach that was developed in the context of the Canadian health system. The purpose of this article is to describe the development of an APLCN model at a Swiss Academic Medical Center as part of a specialized Thoracic Cancer Center and to evaluate the applicability of PEPPA framework in this process. METHOD: In order to develop and implement the APLCN role, we applied the first seven phases of the PEPPA framework. RESULTS: This article spreads the applicability of the PEPPA framework for an APLCN development. This framework allowed us to i) identify key components of an APLCN model responsive to lung cancer patients' health needs, ii) identify role facilitators and barriers, iii) implement the APLCN role and iv) design a feasibility study of this new role. CONCLUSIONS: The PEPPA framework provides a structured process for implementing novel Advanced Practice Nursing roles in a local context, particularly where such roles are in their infancy. Two key points in the process include assessing patients' health needs and involving key stakeholders.

Combining non-invasive methods for assessment of liver fibrosis.

Non-invasive markers of liver fibrosis, including biochemical scores using simple biochemical parameters and transient elastography (TE), have been developed over the past decade to either replace or reduce the need for liver biopsy (LB) in the assessment of liver fibrosis. Although their diagnostic accuracy in liver fibrosis is promising, around 20% of patients are likely to be misclassified if these tests or LB are used alone. However, using a combination of several biochemical scores (Fibropaca algorithm, Leroy algorithm) or one biochemical score with TE (Bordeaux algorithm) will increase diagnostic accuracy for fibrosis and reduce the need for LB. Stepwise combination algorithms of non-invasive scores (SAFE biopsy) also improve the diagnostic performance in chronic hepatitis C (CHC) compared with the use of a single non-invasive score. Other sequential stepwise algorithms have been developed in CHC with similar performance results. Comparisons of different combinations of non-invasive methods indicate that the SAFE biopsy, Fibropaca algorithm and Bordeaux algorithm are excellent and comparable in the non-invasive diagnosis of liver fibrosis in HCV patients, and will markedly reduce the need for LB. They may also be useful in clinical practice and particularly for large-scale screening of HCV patients.

[New perspective in chronic hepatitis B therapy]. / Traitement de l'hépatite chronique B : nouvelles perspectives.

New antiviral drugs, therapeutic vaccines and immunotherapies are interesting therapeutic option for treatment of chronic hepatitis B. Tenofovir disoproxil fumarate and clevudine are very effective in suppressing viral load with lack of resistance at short term. However antiviral drug rarely eliminate the virus. Immunotherapies by inducing HBV - specific T-cell responses may contribute to virus control. Adoptive T-cell therapy is an interesting approach to eliminate persistently infected cells. Therapeutic vaccines with either protein-based or DNA vaccines induce an HBV - specific T-cell responses leading to a more often transient decrease of viral load. Combination of antiviral drug and therapeutic vaccines may be an interesting therapeutic option. However additional larger scale and more systematic studies of the understanding of HBV specific T-cell response have to be performed in order to select which patient can benefit of such therapies.

Optimized stepwise combination algorithms of non-invasive liver fibrosis scores including Hepascore in hepatitis C virus patients.

BACKGROUND: Non-invasive liver fibrosis scores such as Hepascore (HS) have been proposed as an alternative to liver biopsy in hepatitis C virus (HCV)-infected patients. AIM: To validate HS as an alternative to liver biopsy and Fibrotest (FT) and propose five optimized combination algorithms to improve diagnostic accuracy. METHODS: The cohort included 467 patients with HCV. There were 274/467 (59%) men, and mean age was 47 +/- 12 years. RESULTS: Hepascore area under ROC curves (AUC) for > or =F2, F3F4 and F4 diagnosis were 0.82, 0.84 and 0.90 respectively, in the same range as FT. HS and FT were concordant in 387/467 (82%) for fibrosis staging. Among these patients, 342/387 (88%) were concordant with liver biopsy. AUCs of aspartate aminotransferase (AST) to Platelets Ratio Index (APRI) and Forns for > or =F2 were 0.76 and 0.73 (0.65-0.79) respectively. The algorithm combining APRI and HS had the highest rate of avoided liver biopsies (45%) with a high diagnostic accuracy (91%). CONCLUSIONS: Hepascore is an accurate non-invasive marker for > or =F2 and F4 diagnosis in HCV patients. In a pragmatic approach, a stepwise optimized algorithm combining APRI and FT or HS considerably increases diagnostic accuracy and avoided liver biopsies.

[Neuroschistosomiasis: a challenging diagnosis]. / Neuroesquistosomiasis: un reto para el diagnóstico.

INTRODUCTION: Neuroschistosomiasis is an uncommon and under diagnosed disease in our country because of the no clinical suspicion. The most common neurological manifestations are epileptic seizures as central nervous system involvement or different types of myelopathies: transverse myelitis, myeloradiculopathy, cauda equina syndrome or Brown-Sequard syndrome. CASE REPORT: A 27 years-old male from an endemic area, with atypical neurological affectation as he presented myelopathy and multifocal neuritis. Diagnosis was based on the epidemiological exposure datums, the myelopathy, the positive serological studies for Schistosoma haematobium, no detection of other parasitic infections and the clinical and radiological improvement after treatment. Cervical and thoracic magnetic resonance showed areas of hyper signal in T2 as it was described in other cases. It was detected S. haematobium in the bladder, the rest of serological and microbiological studies were negative. Besides, eosinophils on the biopsy of sural nerve orientative to parasitic etiology. CONCLUSION: In patient with myelopathy or another unexplained neurological manifestation we have to suspect neuroschistosomiasis. In a world where migrations and travels are so frequent we have to think in this type of diseases.

Neuroesquistosomiasis: un reto para el diagnóstico / Neurochistosomiasis: a challenging diagnosis

Introducción. La neuroesquistosomiasis es una entidad poco frecuente e infradiagnosticada en nuestro medio por la falta de sospecha clínica. Las formas más habituales de presentación son afectación cerebral o distintas variantes de mielopatías: mielitis transversa, mielorradiculopatía, síndrome de cola de caballo, síndrome de Brown-Séquard. Caso clínico. Varón de 27 años oriundo de zona endémica, con afectación neurológica atípica, pues presenta sintomatología medular y neuropatía multifocal. Los datos epidemiológicos de exposición, la clínica de mielopatía, la serología positiva para Schistosoma haematobium, el descarte de otras posibles parasitosis y la mejoría tanto clínica como radiológica tras el tratamiento nos han permitido llegar al diagnóstico. Las imágenes cervicales y dorsales observadas en la resonancia magnética son similares a las descritas en otras ocasiones. En la investigación etiológica se detecta S. haematobium vesical, siendo el resto de serologías y análisis microbiológicos negativos. Además la presencia de eosinófilos en la biopsia del nervio sural orienta hacia el origen parasitario de dicha afectación. Conclusión. Ante un paciente con mielopatía u otra afectación neurológica no explicada debemos sospechar neuroesquistomiasis. En un mundo donde las migraciones y los viajes son tan frecuentes, cada día debemos pensar más en este tipo de enfermedades de origen tropical

Introduction. Neuroschistosomiasis is an uncommon and under diagnosed disease in our country because of the no clinical suspicion. The most common neurological manifestations are epileptic seizures as central nervous system involvement or different types of myelopathies: transverse myelitis, myeloradiculopathy, cauda equina syndrome or Brown-Séquard syndrome. Case report. A 27 years-old male from an endemic area, with atypical neurological affectation as he presented myelopathy and multifocal neuritis. Diagnosis was based on the epidemiological exposure datums, the myelopathy, the positive serological studies for Schistosoma haematobium, no detection of other parasitic infections and the clinical and radiological improvement after treatment. Cervical and thoracic magnetic resonance showed areas of hyper signal in T2 as it was described in other cases. It was detected S. haematobium in the bladder, the rest of serological and microbiological studies were negative. Besides, eosinophils on the biopsy of sural nerve orientative to parasitic etiology. Conclusion. In patient with myelopathy or another unexplained neurological manifestation we have to suspect neuroschistosomiasis. In a world where migrations and travels are so frequents we have to think in this type of diseases

Validation and comparison of indexes for fibrosis and cirrhosis prediction in chronic hepatitis C patients: proposal for a pragmatic approach classification without liver biopsies.

Noninvasive indexes have been developed to predict fibrosis staging. The aim of this study was to assess the diagnostic accuracy of these indexes in comparison with liver histology in hepatitis C virus (HCV)-infected patients. A total of 235 consecutive patients with HCV infection from the Fibropaca multicentre independent study were included in this paper. FibroTest (FT), aspartate aminotransferase to platelet ratio index (APRI) and Forns score were assessed in the cohort and compared with liver histology performed on the same day. The main end point was the area under characteristic curves (AUCs) for the diagnosis of significant fibrosis (F2-F4) and cirrhosis (F4) by the METAVIR classification. Mean age was 46 (+/-11) years, 55% were males, 42% (n = 99) had significant fibrosis (F2-F4) and 7% (n = 16) had cirrhosis (F4). For the diagnosis of significant fibrosis, respective AUCs of FT, APRI and Forns score were 0.81 (95% confidence interval: 0.76-0.86), 0.71 (0.67-0.79) and 0.76 (0.70-0.82); for cirrhosis prognosis, AUCs of FT and APRI were 0.82 (0.77-0.87) and 0.81 (0.76-0.86) (AUCs not significantly different). Using each index independently, all patients were classified by FT, 214 (91%) patients were classified by APRI and 129 (55%) by Forns score. There were significantly more cases of discordances between APRI and liver biopsy than between FT or Forns score and liver biopsy (P < 0.05). Performing all scores (FT, Forns and APRI) without liver biopsy allowed fibrosis to be well evaluated in 191 patients (81.3%), including patients with FT failure. Liver biopsy remained mandatory to evaluate fibrosis in 44 patients (18.7%). Our study shows that performing all the tests and liver biopsy improves the diagnostic accuracy for liver fibrosis in chronic hepatitis C patients without patent comorbidities. The combination of all tests with liver biopsy allowed 225/235 (96%) patients to be correctly classified. The combination of all tests without liver biopsy allowed 191/235 (81.3%) patients to be correctly classified; liver biopsy remained mandatory in some patients (18.7%).

Adjustable maintenance dosing with budesonide/formoterol in a single inhaler provides effective asthma symptom control at a lower dose than fixed maintenance dosing.

Asthma guidelines suggest a stepwise approach to maintenance pharmacological treatment of persistent asthma until control is attained, and a 3 month review of the fixed maintenance dosing for step-up or step-down adjustment. This 12-week study compared the efficacy and safety of budesonide/formoterol in a single inhaler (Symbicort Turbuhaler 160/4.5 or 80/4.5 microg) given as adjustable maintenance or fixed maintenance dosing. Patients (n = 2358) were randomised to budesonide/formoterol fixed maintenance dosing (two inhalations bid) or adjustable maintenance dosing (two inhalation bid; stepping up to four inhalations bid if asthma worsened for a maximum of 14 days; stepping down to two inhalations once nocte or one inhalation bid if symptoms were controlled) for 12 weeks, following a 4-week run-in period on budesonide/formoterol two inhalations bid. Primary efficacy variables were frequency of asthma exacerbations and changes in patients' asthma symptom severity. Secondary variables were asthma control, safety and health economics. Both adjustable maintenance dosing and fixed maintenance dosing were associated with similar low frequency of exacerbations (5% both groups; ns) and similarly improved lung function, with similarly fewer nocturnal awakenings and less asthma symptoms compared with the mean value of the run-in period. However, patients on adjustable maintenance dosing used 24% fewer study drug compared with fixed maintenance dosing (2.95 versus 3.86 inhalations daily; p < 0.0001) and incurred in a significant (p <0.0001) reduction in total costs (direct+indirect) compared with fixed maintenance dosing. In conclusion, adjustable maintenance dosing with budesonide/formoterol effectively controls asthma at a reduced drug load with lower costs than fixed maintenance dosing.

Lack of specificity of endoglin expression for tumor blood vessels.

A monoclonal antibody (MAb; A11) has been raised following mouse immunization with cultured human microvascular endothelial cells. The MAb showed a strong positivity within tumor vessels in glioblastoma and breast carcinoma samples, and the distribution was consistent with antigen association with vascular endothelial cells. A purification procedure of the antigen was developed starting from DG-RSV-LT-2, an immortalized human endothelial cell line. Molecular mass, N-terminal sequence of the purified antigen and localization on endothelial cell surface allowed identification with human endoglin (CD105). Flow cytometry analysis of a group of normal and transformed cell lines showed that, besides endothelial cells and myelocytic leukemia cells already shown to be positive, fetal fibroblasts, choriocarcinoma, fibrosarcoma and rhabdomyosarcoma cell lines were also positive for this antigen. Immunohistochemic analysis of several normal adult tissues revealed a more extensive presence of the antigen in normal vessels compared to that described with previously characterized antibodies. In fact, even though the staining was weaker than in tumor tissues, all tissues were found to be positive, at least in microvessels, except for normal breast. Moreover, in some tissues (glands and reproductive tract) a positive reaction was observed in the stroma. Since endoglin has been proposed as a possible target for antiangiogenic therapy in tumor patients and our data demonstrate a sizable amount of endoglin in normal vessels and stroma, its clinical use should be carefully reevaluated.

Budd-Chiari syndrome secondary to intracardiac extension of hepatocellular carcinoma. Two cases treated by radical resection.

Two young women presenting Budd-Chiari syndrome as the primary manifestation of hepatocellular carcinoma with intracardiac extension were treated by debulking of the atrium and inferior vena cava under extracorporeal circulation and major hepatectomy. The first patient who was treated in a single procedure died during the immediate postoperative period. The second patient who was treated in two steps died of meningeal and pulmonary metastases 12 months later. Clinical findings and surgical strategy for this rare condition are discussed in the light of 6 previously reported surgical cases.

Smoking cessation as a therapeutic and preventive intervention: a meeting report.

In November 2000, a meeting took place on "Smoking cessation as a therapeutic and preventive intervention". The venue of the meeting was Venice, in the old Monastery of the Isola San Giorgio, and it was jointly organised by the Italian Association of Hospital Pulmonologists (AIPO) and the European Section of the Society for Research on Nicotine and Tobacco (SRNT--Europe). The meeting was also sponsored by the European Respiratory Society (ERS). The importance of the topic cannot be underestimated. According to the World Health Organisation (WHO) tobacco smoking is the most important cause of preventable death in the industrialised world. When tobacco smoking constitutes a repetitive and compulsive behaviour, for instance when a person continues smoking when suffering from a smoking related disease, it is due to tobacco dependence, which both WHO and the American Psychiatric Association classify as a disease. Tobacco smoking is not only a disease in itself but can also cause other diseases, such as chronic obstructive lung disease, lung cancer and cardiovascular disease, and can worsen pre-existent disease, e.g. asthma. In the WHO European region, according to WHO estimates, tobacco smoking causes at least 1,200,000 deaths each year (14% of all deaths). So far, a preventive strategy based on protection of children and adolescents from initiation has not worked in decreasing the prevalence among young generations. Even with the best educational programs success is partial and ephemeral. Smoking cessation with behavioural and pharmacological aid is a well established therapeutic intervention, supported by strong scientific evidence. But smoking cessation can also be a preventive intervention, because it can reduce the prevalence of smokers in a community. Obviously, smoking cessation is to be used together with all other interventions recognized as effective in tobacco control (cigarette and tobacco product pricing, regulatory approaches, smoking bans, health education).

Iatrogenic dissection of the portal vein during TIPS procedure.

Dissection of the portal vein is a rare entity which has been rarely described during transjugular intrahepatic portosystemic shunt (TIPS) procedure. We report three cases of dissection during this procedure and their complications. One dissection was immediately treated with coaxial stents. The two others were complicated either by a thrombus or by a false aneurysm. In the first case a second parallel stent was used to treat this complication. The patient with the portal vein false aneurysm was transplanted 4 days after this diagnosis. Portal vein dissection in TIPS procedure appeared to be less rare than has been reported and must be considered as a potential cause of TIPS dysfunction.

Absence of hepatitis C genome in semen of infected men by polymerase chain reaction, branched DNA and in situ hybridization.

BACKGROUND/AIMS: The presence or absence of hepatitis C virus (HCV) RNA in the semen of infected man remains controversial, mainly due to technical difficulties associated with nucleic acid detection. The aims of this study were to assess the presence of HCV RNA in spermatozoa and in seminal fluid using different polymerase chain reaction (PCR)- and non-PCR-dependent methods and, in the case of HCV presence, to correlate this detection with the viraemia. METHODS: Serum and semen from 25 chronically infected hepatitis C patients were studied. The semen was separated into spermatozoa and seminal fluid and HCV RNA was analysed in the two fractions using RT-PCR and branched DNA. The presence of HCV RNA in pelleted cells was also assessed using in situ hybridization. RESULTS: All three approaches failed to demonstrate HCV RNA in semen. The presence of an inhibitor of the PCR was demonstrated in seminal fluid but not in spermatoza. CONCLUSION: Our results confirmed the lack of detection of HCV RNA in semen by PCR- and non-PCR-dependent techniques and support the view that viral contamination in semen remains, if present, at a very low level. Nevertheless, epidemiological studies are required to definitively assess the absence of sexual transmission of HCV

The angiogenesis marker ED-B+ fibronectin isoform in intracranial meningiomas.

Fibronectins (FNs), adhesive glycoproteins mainly expressed in the extracellular matrix, are polymorphic molecules whose various isoforms are dependent on alternative splicing patterns. The isoform containing the ED-B sequence and occurring in foetal and neoplastic tissues (oncofoetal or B+FN) has been previously recognized as a marker for angiogenesis. The distribution of this isoform was analyzed in a consecutive series of 134 surgically obtained intracranial meningiomas, using specific monoclonal antibodies. Oncofoetal FN was found to be widely distributed in the vessels of anaplastic meningiomas, with its expression being restricted in the vasculature of the typical subtypes. and absent in the neighbouring cerebral tissue. The ubiquitous vascular expression of B+FN in meningiomatous malignancies might provide a potential target for the in vivo delivery of angiosuppressive agents.

A high-affinity human antibody that targets tumoral blood vessels.

Angiogenesis is a characteristic feature of many aggressive tumors and of other relevant disorders. Molecules capable of specifically binding to new-forming blood vessels, but not to mature vessels, could be used as selective vehicles and would, therefore, open diagnostic and therapeutic opportunities. We have studied the distribution of the ED-B oncofetal domain of fibronectin, a marker of angiogenesis, in four different tumor animal models: the F9 murine teratocarcinoma, SKMEL-28 human melanoma, N592 human small cell lung carcinoma, and C51 human colon carcinoma. In all of these experimental models we observed accumulation of the fibronectin isoform containing the ED-B domain around neovascular structures when the tumors were in the exponentially growing phase, but not in the slow-growing phase. Then we performed biodistribution studies in mice bearing a subcutaneously implanted F9 murine teratocarcinoma, using a high-affinity human antibody fragment (L19) directed against the ED-B domain of fibronectin. Radiolabeled L19, but not an irrelevant anti-lysozyme antibody fragment (D1.3), efficiently localizes in the tumoral vessels. The maximal dose of L19 accumulated in the tumor was observed 3 hours after injection (8.2% injected dose per gram). By virtue of the rapid clearance of the antibody fragment from the circulation, tumor-to-blood ratios of 1.9, 3.7, and 11.8 were obtained at 3, 5, and 24 hours, respectively. The tumor-targeting performance of L19 was not dose-dependent in the 0.7 to 10 microg range of injected antibody. The integral of the radioactivity localized in tumoral vessels over 24 hours was greater than 70-fold higher than the integral of the radioactivity in blood over the same time period, normalized per gram of tissue or fluid. These findings quantitatively show that new-forming blood vessels can selectively be targeted in vivo using specific antibodies, and suggest that L19 may be of clinical utility for the immunoscintigraphic detection of angiogenesis in patients.