[Patient's own medications in a Swiss regional hospital: where are we and where should we go?] / Gestion du traitement personnel des patients dans un hôpital régional suisse : état des lieux et propositions d'actions à mettre en œuvre.

OBJECTIVE: The use of patient's own medications (POMs) during inpatient admissions may represent a risk if not adequately supervised. The objective of this work was: (i) to assess the management of POMs in our hospital, and (ii) to identify actions to assure this practice. METHODS: A questionnaire survey was conducted among caregivers of the medical, surgery and geriatric units of a Swiss regional hospital. Six criteria for appropriate management of POMs were identified from the literature and internal consensus. Based on this survey and data from literature, the investigators identified relevant actions to be implemented for optimizing the management of POMs. RESULTS: Out of the 21 included units, 3 already set an inner written POMs policy, and 3 managed POM in accordance with selected criteria. The main issues were that POMs were mainly stored in the patient's room, and that quality criteria were not systematically checked before POMs' administration. POMs were mainly used to ensure continuity of treatment. Two thirds of the units systematically returned POMs to the patients upon discharge, but rarely sorted them out before recovery. Ten actions were identified to secure the management of POMs. CONCLUSION: These results confirm that POMs are commonly used and indicate a potential for improvement in the management of POMs in our hospital. An institutional guideline is now planned to support the implementation of the identified actions.

Cartilaginous choristoma of the oral cavity: a report of two cases.

A choristoma is a tumour-like mass of normal cells in an abnormal location. Intra-oral choristomas are rare lesions. We report on two cases of cartilaginous choristoma, one in the tongue, the most frequently involved oral structure, and another in the upper oral vestibule. We discuss the lesion's clinical features and their differential diagnosis. The widely accepted metaplastic, embryonal and tumoral histopathologenetic theories are discussed. Surgical excision is the treatment of choice, and no recurrence has been reported.

Tumoral environment triggers transcript anomalies in established tumors: induction of altered gene expression and of aberrant, truncated and B2 repeat-containing gene transcripts.

In addition to eugenetic changes, cancerous cells exhibit extensive modifications in the expression levels of a variety of genes. The phenotypic switch observed after inoculation of T lymphoma cells into syngenic mice illustrates the active participation of tumoral environment in the induction of an aberrant gene expression pattern. To further substantiate this contribution, we performed polymerase chain reaction (PCR)-based subtraction suppression hybridization (SSH) to identify genes that are differentially expressed in tumor-derived EL4/13.3 cells compared to the same cells isolated from cultures. Besides a number of unknown genes, the subtracted library contained several known genes that have been reported to be expressed at increased levels in tumors and/or to contribute to carcinogenesis. Apart from clones representing translated transcripts, the subtracted library also contained a high number of clones representing B2 repeat elements, viz. short interspersed repetitive elements that are transcribed by RNA polymerase III. Northern blotting confirmed the induction of B2 transcripts in tumor tissue and also revealed induction of chimeric, B2 repeat-containing mRNA. The appearance of chimeric transcripts was accompanied by aberrant, shorter-than-full-length transcripts, specifically from upregulated genes. Accordingly, in addition to altered gene expression, tumoral environmental triggers constitute a potent mechanism to create an epigenetic diversity in cancers by inducing extensive transcript anomalies.

Longitudinal follow-up of TTS-fentanyl use in patients with cancer-related pain: results of a compassionate-use study with special focus on elderly patients.

GOALS OF THE WORK: This open compassionate-use prospective registration study evaluated the tolerability, ease of use and applied doses of transdermal (TTS) fentanyl in adult patients with cancer-related pain requiring strong opioid analgesia. Elderly patients were particularly focussed on. PATIENTS AND METHODS: Previous pain medication was converted to an appropriate dose of TTS-fentanyl. Immediate-release morphine rescue medication was allowed as needed for breakthrough pain. Dose adjustments of TTS-fentanyl, rescue morphine requirements, the ease of use and side-effects were assessed monthly, with special emphasis paid to the severity of constipation and the use of laxatives. MAIN RESULTS: A total of 663 patients with cancer-related pain, including 8% opioid-naive patients, were enrolled; 661 patients used at least 1 patch of TTS-fentanyl. Of these, 455 subjects were assessed at baseline and at 1 post-baseline visit at least. Individual treatment ranged from a few days to 2 1/2 years; TTS-fentanyl doses ranged from 25 to 950 microg/h. The major reason for study termination was non-drug-related death (61%). Approximately 40% of patients reported constipation. The frequency of constipation depended on the rescue morphine dose used, but no dose-relationship was found for TTS-fentanyl. Patient acceptance of the patches was high; around 85% of patients rated convenience as good to excellent The ease of use and tolerability of TTS-fentanyl in the elderly patients were comparable to that in the total population, except for a slight increase of non-serious adverse events. CONCLUSIONS: TTS-fentanyl can be applied as long-term therapy to patients with cancer-related pain, including the elderly.

Effect of backyard burning on dioxin deposition and air concentrations.

The influence from open burning of garden and household waste on locally measured dioxin deposition and air concentrations was evaluated in three sets of experiments: the combustion of garden waste in barrels and in open fires, and the incineration of household waste in an empty oil drum. Each set was composed of eight individual experiments over 4 h. Deposition gauges were located 20 m NE, SE, SW and NW with respect to the source and on a background location at 400 m SW. Air samples were taken in the plume with a medium volume sampler equipped with a quartz filter and a polyurethane plug. The results illustrate deposition increments in the wind direction at a distance of 20 m from the source of 0.8 pg TEQ/m2 day for garden waste and 2.5 pg TEQ/m2 day for household waste. Concentrations in the plume were increased by 160-580 fg TEQ/m3 over a period of 12 and 31 h respectively. Expressed at a reference CO2 concentration of 9% this corresponds with a range from 0.8 to 3.6 ng TEQ/m3, which is comparable with a poorly controlled MSWI. Emission factors in the order of magnitude of 4.5 ng TEQ/kg combusted garden waste and 35 ng TEQ/kg burned municipal waste were determined.

A multi-method study on the quality of the nurse work environment in acute-care hospitals: positioning Switzerland in the Magnet hospital research.

BACKGROUND: Magnet hospitals share nurse work environment characteristics associated with superior patient, nurse and financial outcomes. In Switzerland, however, it is uncertain how nurses appraise their work environments. OBJECTIVES: To describe the quality of the nurse work environment in 35 Swiss acute care hospitals and to benchmark findings based on international Magnet hospital research. METHOD: This study used two data sources: (1) the Swiss arm of the RN4CAST study; and (2) a structured literature review. Hospitals were categorised based on Magnet and non-Magnet data. Our outcome variable of interest was the quality of nurse work environment measured with the Practice Environment Scale of the Nurse Work Index (PES-NWI). RESULTS: We reviewed 13 American, Canadian, and Australian studies of acute-care hospitals. Three provided Magnet hospitals' nurse work environment data, and all included non-Magnet hospitals' data. Swiss hospitals' evaluations on nurse work environment quality varied widely, but 25% achieved scores indicating "Magnet nurse work environments". Swiss hospitals' average "Nursing manager ability" subscale scores fulfilled Magnet hospital criteria, although "Nurse participation in hospital affairs" and "Nursing staffing and resource adequacy" scores neared non-Magnet levels. CONCLUSION: On average, our results indicated high quality nurse work environments in Swiss hospitals. Implementing Magnet model organisational principles might be a valuable approach for Swiss acute-care hospitals to both improve mixed and unfavourable nurse work environments and to improve nurse and patient outcomes. National benchmarking of nurse work environments and other nurse-sensitive indicators may facilitate evaluating the impact of current developments in Swiss healthcare.

Analysis of PCDD/Fs and dioxin-like PCBs in atmospheric deposition samples from the Flemish measurement network: correlation between the CALUX bioassay and GC-HRMS.

Since the CALUX (Chemically Activated LUciferase gene eXpression) bioassay is a fast, sensitive and inexpensive tool for the analysis of a high number of samples, the use of this technique in routine analysis of atmospheric deposition samples may be a valuable alternative for GC-HRMS. In this study, a validated CALUX method was used for the analysis of PCDD/Fs and dioxin-like PCBs in more than 90 atmospheric deposition samples for different locations in Flanders. The samples were taken in residential and agricultural areas, where a threshold limit of 21pgWHO-TEQm(-2)d(-1) for the sum of PCDD/Fs and dioxin-like PCBs was set, and in industrial zones and natural reserves, where no official threshold limit is available. The results from the Flemish measurement program showed correlation between CALUX and GC-HRMS for all the samples, originating from the different areas (R(2) of 0.81, 0.53 and 0.64 for dl-PCBs, PCDD/Fs and sum of both fractions, respectively). Median CALUX/GC-HRMS ratios of 2.0, 0.9 and 1.3 were reported for the PCDD/Fs, dioxin-like PCBs and the sum of both fractions, respectively. The results show that the CALUX bioassay is a valuable alternative tool for the classic GC-HRMS analysis of atmospheric deposition samples in the Flemish measurement network.

Analysis of PCDD/Fs and dioxin-like PCBs in atmospheric deposition samples from the Flemish measurement network: Optimization and validation of a new CALUX bioassay method.

Since the CALUX (Chemically Activated LUciferase gene eXpression) bioassay is a fast, sensitive and inexpensive tool for the analysis of a high number of samples, validation of new methods is urgently needed. In this study, a new method for the analysis of PCDD/Fs and dioxin-like PCBs in atmospheric deposition samples with the CALUX bioassay was developed, optimized and validated. The method consists of 4 steps: filtration, extraction, clean up and bioassay analysis. To avoid the use of large amounts of toxic solvents, new techniques were used for filtration and extraction: a C18 filter was used instead of a liquid/liquid extraction and an Accelerated Solvent Extractor (ASE) was used instead of the traditional soxhlet extraction. After pre-oxidation of the sample extract, clean up was done using a multi-layer silica gel column coupled to a carbon column. The PCDD/F and PCB fractions were finally analyzed with the H1L7.5c1 and/or the H1L6.1c3 mouse hepatoma cell lines. The limit of quantification was 1.4pg CALUX-BEQm(-2)d(-1) for the PCBs and 5.6pgCALUX-BEQm(-2)d(-1) for the PCDD/Fs, when using the new sensitive H1L7.5c1 cell line. The GC-HRMS recovery for all PCDD/F congeners was between 55% and 112%, with a mean recovery of 90%. CALUX recoveries of spiked procedural blanks were between the accepted ranges of 80-120%. Repeatability and reproducibility were satisfactory and no interferences from metals were detected. The first results from the Flemish measurement program showed good correlation between CALUX and GC-HRMS.

Palliative care services in Belgium: benefits and shortcomings of a legal framework.

All health services dealing with the terminally ill are called upon to dispense palliative care. We shall, however, be making a distinction between palliative care services and other forms of services: in fact, the main activity of a palliative care service is palliative medicine, which is dispensed by its trained and experienced personnel. In Belgium, the first specialist palliative care services developed autonomously, and the absence of a planning policy isolated them from the rest of the health system. The Belgian health authorities decided to put an end to this situation by legislation: the laws introduced determine the number, mission and modus operandi of the various palliative care services, as well as the links to be established between them (interaction of the home care support team and the mobile function in hospitals or institutions for the elderly and association for cooperation). The following is a presentation and critical analysis of this legislation.

Palliative home care: improving co-operation between the specialist team and the family doctor.

The aim of this study is to ascertain family doctors' opinions of the home care services dispensed by a specialist palliative care team. Fifty-six doctors responded to the questionnaire they had been sent. Ninety-four per cent of them were satisfied with the team's intervention. The highest satisfaction ratings were those for the provision of specialist medical equipment, technical competence and medical support. The lowest ratings were for information coming from the team and for recognition of the practitioner as the primary carer. Among these items, information, regard for the doctor's role and medical support are closely correlated to the practitioners' overall index of satisfaction. The palliative care team answered a mirror questionnaire. It found its availability, its speed of intervention, its technical competence, and its regard for the doctor's role very satisfactory. It was less satisfied with the information, medical support and psychosocial support it provided. Its centres of interest also differed, with the team clearly attributing greater importance to psychosocial support than to technical competence, regard for the role, and information to the practitioner. In conclusion, a survey of this type is a useful and easy way of identifying the aspects that need to be improved on by the palliative care team so as to improve its co-operation with the family physician. But it is of interest only if it forms part of an overall approach whereby, having taken the survey results on board, the team uses them to modify its intervention procedures.

Altered fetal cardiac flow patterns in pure red cell anaemia (the Blackfan-Diamond syndrome).

In a case of fetal anaemia due to pure red cell anaemia (Blackfan-Diamond syndrome), two-dimensional fetal Doppler echocardiography revealed an altered blood flow velocity pattern with entire incorporation of the atrial contraction component in the early passive filling phase of the right ventricle. Intracardiac blood velocities were increased, whereas cardiac output was only moderately increased. The fetal heart rate was normal. It is concluded that in fetal anaemia the compensatory mechanisms are limited and restricted to an increase in stroke volume. The hypothesis that chronic fetal anaemia is associated with 'high output cardiac failure' corresponds well with the present findings. The technique described may prove to be useful in the early diagnosis of fetal anaemia.

Macrophages induce cellular immunity by activating Th1 cell responses and suppressing Th2 cell responses.

Differentiation of naive CD4+ T cells (Th0) into Th1 or Th2 cells determines whether antigen will raise a cellular or a humoral immune response. The maturation pathway chosen by the Th0 cell is often decisive for the outcome of disease and depends among others on the (co-)stimulatory attributes of the APC and the nature and abundance of cytokines provided by the APC and the microenvironment. In this study, we used macrophages, loaded ex vivo with antigen, for inciting Th0 activation and differentiation in vivo. The macrophages were derived from a clonal, immortalized population that both functionally and phenotypically expressed features characteristic of mature macrophages. Injection into syngeneic mice of IFN-gamma-treated, Ag-loaded macrophages induced a primary T cell response, indicated by the occurrence of a proliferative response in vitro after restimulation of splenocytes with Ag. Analysis of the accompanying cytokine secretion revealed high numbers of IFN-gamma-producing Th1 cells and only a few IL-4-secreting Th2 cells. This dominance of Th1 cells had functional implications, reflected in the high titer of Th1 cell-dependent IgG2 Abs and the absence of IgG1, characteristic of humoral immunity. Moreover, administration of Ag-loaded macrophages to mice with an ongoing Th1/Th2 response resulted in a complete suppression of IgG1 production, whereas IgG2 levels remained unaffected. These results demonstrate that macrophages exert APC activity in the organism, strongly skew primary responses to cellular immunity, and in addition suppress an already generated Th2-dependent humoral response, thus characterizing these cells as Th1-oriented APC.

Lipopolysaccharide regulates macrophage fluid phase pinocytosis via CD14-dependent and CD14-independent pathways.

Lipopolysaccharide (LPS) is a mediator of inflammation and septic shock during bacterial infection. Although monocytes and macrophages are highly responsive to LPS, the biological effects of LPS in these cell types are only partially understood. We decided, therefore, to investigate the influence of LPS on macrophage pinocytosis and Fc receptor-mediated endocytosis, two prominent and related macrophage effector functions. We observed that LPS did not greatly influence endocytosis in either macrophages or monocytes, but did exert a dual action on pinocytosis: at lower concentrations (0.1 to 100 ng/mL), LPS caused a decrease in pinocytosis in both macrophages and monocytes, whereas at higher LPS concentrations, enhanced pinocytosis in macrophages was observed. Detoxified LPS was two orders of magnitude less potent in producing these effects. After inhibition of the LPS receptor CD14, the LPS-induced decrease in pinocytosis was absent, and stimulation of pinocytosis at lower LPS concentrations was unmasked. We conclude that LPS can influence pinocytosis via CD14-dependent and CD14-independent signaling pathways. Furthermore, as addition of LPS to macrophages effected pinocytosis but not Fc receptor-mediated endocytosis, these two processes are independently regulated in macrophages.

Quiescence-inducing and antiapoptotic activities of IL-15 enhance secondary CD4+ T cell responsiveness to antigen.

IL-15 shows functional redundancy with IL-2 due to its usage of the beta and gamma c subunit of the IL-2R. Yet, the requirement of IL-15 for an IL-15R alpha chain for high affinity interaction and the separate cellular sources of IL-2 and IL-15 suggest divergent activities for both cytokines. We compared the growth-inducing and proapoptotic or antiapoptotic activities of IL-15 and IL-2 on mature CD4+ T lymphocytes in the presence or absence of TCR occupancy. We found that the nature of IL-15 activity was critically dependent on the activation status of the T cells. In the absence of TCR triggering, IL-15 did not exert the growth factor activity of IL-2, but induced a quiescent phenotype, characterized by maintenance of the cells in the G0/G1 phase of the cell cycle and down-regulation of CD25, CD71, and CD95 expression. In the presence of appropriate TCR engagement, the IL-15-induced quiescent T cells were resistant against TCR-induced cell death and proliferated strongly. IL-2-treated cells, on the contrary, were sensitized to cell death, resulting in a negative feedback on cellular expansion and weak proliferative responsiveness. Consecutive action of IL-15 during the distinct phases of an in vitro immune response markedly increased the cell output of a second antigenic stimulation, as compared with IL-2. These results imply that during immune reactivity in vivo, IL-15 may take over from the transiently available IL-2 the role of survival factor but not of growth factor, hence promoting the long term maintenance of resting, Ag-experienced CD4+ T cells.

Macrophages present pinocytosed exogenous antigen via MHC class I whereas antigen ingested by receptor-mediated endocytosis is presented via MHC class II.

Macrophages present exogenous Ag either via MHC class I or MHC class II molecules. We investigated whether the mode of hemagglutinin (HA) uptake influences the class of MHC molecule by which this Ag is presented. Normally, HA is ingested by receptor-mediated endocytosis, but this may be switched to macropinocytosis and pinocytosis by adding phorbol esters to the cells. This switch resulted in altered intracellular routing of ingested Ag and a transition from Ag presentation via MHC class II molecules to presentation via MHC class I molecules. Similarly, inhibition of receptor-mediated HA endocytosis, by treating the cells with the HA receptor destroying enzyme neuraminidase, abrogated Ag presentation via MHC class II molecules and induced presentation via MHC class I molecules. If, however, under these conditions, receptor-mediated uptake of HA was restored, by virtue of HA/anti-HA Ab interaction and subsequent uptake of HA via the Fc receptor, presentation via MHC class II was restored as well, whereas presentation of HA via MHC class I molecules was no longer detectable. We conclude that in macrophages the mode of Ag uptake is decisive in determining via which class of MHC molecules Ag is presented: pinocytosis and macropinocytosis produce exclusive presentation of exogenous Ag via MHC class I molecules whereas receptor-mediated endocytosis leads exclusively to presentation via class II molecules.

Interleukin-15 redirects the outcome of a tolerizing T-cell stimulus from apoptosis to anergy.

Clonal deletion and anergy are 2 mechanisms used by the immune system to establish peripheral tolerance. In vitro, these mechanisms are induced in T lymphocytes by triggering the T-cell receptor (signal 1) in the absence of costimulation (signal 2). T-cell clones have been shown either to become anergic or to die in response to signal 1 alone; yet the factors that govern this choice remain unknown. This study evaluated the influence of the cytokines interleukin (IL)-2 and IL-15 on the response of the Th1 clone hemagglutinin (T-HA) to signal 1, delivered by stimulation with immobilized anti-CD3 monoclonal antibody (mAb). The response induced by immobilized anti-CD3 mAb was dependent on the cytokine milieu; in the presence of IL-2, T-HA cells were subject to apoptosis, whereas in the presence of IL-15 the cells remained viable but showed proliferative unresponsiveness. After release from the anti-CD3 stimulus, the IL-15-rescued T-HA cells regained responsiveness to IL-2 and IL-15 growth factor activity. However, they were unable to proliferate when stimulated with their cognate antigen presented by professional antigen-presenting cells (signal 1 plus 2) and thus had acquired an anergic phenotype. These data assign a novel function to the previously reported antiapoptotic activity of IL-15, namely, the capacity to redirect the T-cell response to partial stimulation from clonal deletion to anergy. Furthermore, they emphasize that the cytokine environment can critically influence the outcome of a tolerizing stimulus.

Differentiation of EL4 lymphoma cells by tumoral environment is associated with inappropriate expression of the large chondroitin sulfate proteoglycan PG-M and the tumor-associated antigen HTgp-175.

Progression to malignancy of transformed cells involves complex genetic alterations and aberrant gene expression patterns. While aberrant gene expression is often caused by alterations in individual genes, the contribution of the tumoral environment to the triggering of this gene expression is less well established. The stable but heterogeneous expression in cultured EL4/13 cells of a novel tumor-associated antigen, designated as HTgp-175, was chosen for the investigation of gene expression during tumor formation. Homogeneously HTgp-175-negative EL4/13 cells, isolated by cell sorting or obtained by subcloning, acquired HTgp-175 expression as a result of tumor formation. The tumorigenicity of HTgp-175-negative vs. HTgp-175-positive EL4 variants was identical, indicating that induction but not selection accounted for the phenotypic switch from HTgp-175-negative to HTgp-175-positive. Although mutagenesis experiments showed that the protein was not essential for tumor establishment, tumor-derived cells showed increased malignancy, linking HTgp-175 expression with genetic changes accompanying tumor progression. This novel gene expression was not an isolated event, since it was accompanied by ectopic expression of the large chondroitin sulfate proteoglycan PG-M and of normal differentiation antigens. We conclude that signals derived from the tumoral microenvironment contribute significantly to the aberrant gene expression pattern of malignant cells, apparently by fortuitous activation of differentiation processes and cause expression of novel differentiation antigens as well as of inappropriate tumor-associated and ectopic antigens.

Cathepsin B-mediated activation of the proinflammatory caspase-11.

Members of the caspase (CASP) family of cysteine proteases can be subdivided in proapoptotic caspases and proinflammatory caspases. Whereas the apical activation pathways for the caspases that are involved in the execution of the apoptotic process are beginning to be understood, the pathways that lead to the activation of proinflammatory caspases are still largely unknown. Analysis of subcellular fractions for their ability to process and activate several caspases in vitro led to the identification of lysosomes as the source for a protease that could proteolytically activate the proinflammatory CASP-11. Although this lysosomal activity was sensitive to caspase inhibitors, affinity purification with the biotinylated broad spectrum caspase inhibitor z-VAD.fmk revealed the CASP-11 activating protease as cathepsin B. Activation of CASP-11 by cathepsin B as well as its sensitivity to several caspase inhibitors was further confirmed with purified proteases. Similar to the role of mitochondrial factors in the activation of proapoptotic caspases, our results suggest a potential role for lysosomes and cathepsin B as activators of specific proinflammatory caspases. In addition, the aspecific inhibition of cathepsin B by so-called specific caspase inhibitors implicates that results obtained with these inhibitors should be interpreted with care.