Consensus Report: 2nd European Workshop on Tobacco Use Prevention and Cessation for Oral Health Professionals

Tobacco use has been identified as a major risk factor for oral disorders such as cancer and periodontal disease. Tobacco use cessation (TUC) is associated with the potential for reversal of precancer, enhanced outcomes following periodontal treatment, and better periodontal status compared to patients who continue to smoke. Consequently, helping tobacco users to quit has become a part of both the responsibility of oral health professionals and the general practice of dentistry. TUC should consist of behavioural support, and if accompanied by pharmacotherapy, is more likely to be successful. It is widely accepted that appropriate compensation of TUC counselling would give oral health professionals greater incentives to provide these measures. Therefore, TUC-related compensation should be made accessible to all dental professionals and be in appropriate relation to other therapeutic interventions. International and national associations for oral health professionals are urged to act as advocates to promote population, community and individual initiatives in support of tobacco use prevention and cessation (TUPAC) counselling, including integration in undergraduate and graduate dental curricula. In order to facilitate the adoption of TUPAC strategies by oral health professionals, we propose a level of care model which includes 1) basic care: brief interventions for all patients in the dental practice to identify tobacco users, assess readiness to quit, and request permission to re-address at a subsequent visit, 2) intermediate care: interventions consisting of (brief) motivational interviewing sessions to build on readiness to quit, enlist resources to support change, and to include cessation medications, and 3) advanced care: intensive interventions to develop a detailed quit plan including the use of suitable pharmacotherapy. To ensure that the delivery of effective TUC becomes part of standard care, continuing education courses and updates should be implemented and offered to all oral health professionals on a regular basis.

Anti insulin-like growth factor I receptor immunoliposomes: a single formulation combining two anticancer treatments with enhanced therapeutic efficiency

Context: Through overexpression and aberrant activation in many human tumors, the IGF system plays a key role in tumor development and tumor cell proliferation. Different strategies targeting IGF-I receptor (IGFI-R) have been developed, and recent studies demonstrated that combined treatments with cytostatic drugs enhance the potency of anti-IGFI-R therapies. Objective: The objective of the study was to examine the IGFI-R expression status in neuroendocrine tumors of the gastroenteropancreatic system (GEP-NETs) in comparison with healthy tissues and use potential overexpression as a target for novel anti-IGFI-R immunoliposomes. Experimental Design: A human tumor tissue array and samples from different normal tissues were investigated by immunohistochemistry. An IGFI-R antagonistic antibody (1H7) was coupled to the surface of sterically stabilized liposomes loaded with doxorubicin. Cell lines from different tumor entities were investigated for liposomal association studies in vitro. For in vivo experiments, neuroendocrine tumor xenografts were used for evaluation of pharmacokinetic and therapeutic properties of the novel compound. Results: Immunohistochemistry revealed significant IGFI-R overexpression in all investigated GEP-NETs (n = 59; staining index, 229.1 +/- 3.1%) in comparison with normal tissues (115.7 +/- 3.7%). Furthermore, anti-IGFI-R immunoliposomes displayed specific tumor cell association (44.2 +/- 1.6% vs. IgG liposomes, 0.8 +/- 0.3%; P < 0.0001) and internalization in human neuroendocrine tumor cells in vitro and superior antitumor efficacy in vivo (life span 31.5 +/- 2.2 d vs. untreated control, 19 +/- 0.6, P = 0.008). Conclusion: IGFI-R overexpression seems to be a common characteristic of otherwise heterogenous NETs. Novel anti-IGFI-R immunoliposomes have been developed and successfully tested in a preclinical model for human GEP-NETs. Moreover in vitro experiments indicate that usage of this agent could also present a promising approach for other tumor entities.

Antibiotic use in adult outpatients in Switzerland in relation to regions, seasonality and point of care tests

The use of antibiotics is highest in primary care and directly associated with antibiotic resistance in the community. We assessed regional variations in antibiotic use in primary care in Switzerland and explored prescription patterns in relation to the use of point of care tests. Defined daily doses of antibiotics per 1000 inhabitants (DDD(1000pd) ) were calculated for the year 2007 from reimbursement data of the largest Swiss health insurer, based on the anatomic therapeutic chemical classification and the DDD methodology recommended by WHO. We present ecological associations by use of descriptive and regression analysis. We analysed data from 1 067 934 adults, representing 17.1% of the Swiss population. The rate of outpatient antibiotic prescriptions in the entire population was 8.5 DDD(1000pd) , and varied between 7.28 and 11.33 DDD(1000pd) for northwest Switzerland and the Lake Geneva region. DDD(1000pd) for the three most prescribed antibiotics were 2.90 for amoxicillin and amoxicillin-clavulanate, 1.77 for fluoroquinolones, and 1.34 for macrolides. Regions with higher DDD(1000pd) showed higher seasonal variability in antibiotic use and lower use of all point of care tests. In regression analysis for each class of antibiotics, the use of any point of care test was consistently associated with fewer antibiotic prescriptions. Prescription rates of primary care physicians showed variations between Swiss regions and were lower in northwest Switzerland and in physicians using point of care tests. Ecological studies are prone to bias and whether point of care tests reduce antibiotic use has to be investigated in pragmatic primary care trials.

[Recombinant proteins as therapeutic compounds in clinical oncology]

The in vitro production of recombinant protein molecules has fostered a tremendous interest in their clinical application for treatment and support of cancer patients. Therapeutic proteins include monoclonal antibodies, interferons, and haematopoietic growth factors. Clinically established monoclonal antibodies include rituximab (targeting CD20-positive B-cell lymphomas), trastuzumab (active in HER-2 breast and gastric cancer), and bevacizumab (blocking tumor-induced angiogenesis through blockade of vascular-endothelial growth factor and its receptor). Interferons have lost much of their initial appeal, since equally or more effective treatments with more pleasant side effects have become available, for example in chronic myelogenous leukaemia or hairy cell leukaemia. The value of recombinant growth factors, notably granulocyte colony stimulating factor (G-CSF) and erythropoietin is rather in the field of supportive care than in targeted anti-cancer therapy. Adequately powered clinical phase III trials are essential to estimate the true therapeutic impact of these expensive compounds, with appropriate selection of clinically relevant endpoints and sufficient follow-up. Monoclonal antibodies, interferons, and growth factors must also, and increasingly so, be subjected to close scrutiny by appropriate cost-effectiveness analyses to ensure that their use results in good value for money. With these caveats and under the condition of their judicious clinical use, recombinant proteins have greatly enriched the therapeutic armamentarium in clinical oncology, and their importance is likely to grow even further.

Current state of evidence on 'off-label' therapeutic options for systemic lupus erythematosus, including biological immunosuppressive agents, in Germany, Austria and Switzerland--a consensus report

Systemic lupus erythematosus (SLE) can be a severe and potentially life-threatening disease that often represents a therapeutic challenge because of its heterogeneous organ manifestations. Only glucocorticoids, chloroquine and hydroxychloroquine, azathioprine, cyclophosphamide and very recently belimumab have been approved for SLE therapy in Germany, Austria and Switzerland. Dependence on glucocorticoids and resistance to the approved therapeutic agents, as well as substantial toxicity, are frequent. Therefore, treatment considerations will include 'off-label' use of medication approved for other indications. In this consensus approach, an effort has been undertaken to delineate the limits of the current evidence on therapeutic options for SLE organ disease, and to agree on common practice. This has been based on the best available evidence obtained by a rigorous literature review and the authors' own experience with available drugs derived under very similar health care conditions. Preparation of this consensus document included an initial meeting to agree upon the core agenda, a systematic literature review with subsequent formulation of a consensus and determination of the evidence level followed by collecting the level of agreement from the panel members. In addition to overarching principles, the panel have focused on the treatment of major SLE organ manifestations (lupus nephritis, arthritis, lung disease, neuropsychiatric and haematological manifestations, antiphospholipid syndrome and serositis). This consensus report is intended to support clinicians involved in the care of patients with difficult courses of SLE not responding to standard therapies by providing up-to-date information on the best available evidence.

Therapeutic hypothermia in term infants after perinatal encephalopathy: The last 5 years in Switzerland

Background: Therapeutic hypothermia (TH) following perinatal asphyxial encephalopathy in term infants improves mortality and neurodevelopmental outcome. In Europe, most neonatal units perform active cooling whereas in Switzerland passive cooling is predominantly used. Aims: (i) To determine how many infants were cooled within the last 5 years in Switzerland, (ii) to assess the cooling methods, (iii) to evaluate the variation of temperature of different cooling methods, and (iv) to evaluate the use of neuromonitoring. Study design: Retrospective cohort study. Patients: Notes of all cooled term infants between March 2005 and December 2010 in 9 perinatal and two paediatric intensive care centres were retrospectively reviewed. Active cooling was compared to passive cooling alone and to passive cooling in combination with gel packs. Results: 150 infants were cooled. Twenty-seven (18.2%) were cooled actively, 34 (23%) passively and 87 (58.8%) passively in combination with gel packs. Variation of temperature was significantly different between the three methods. Passive cooling had a significant higher variation of temperature (SD of 0.89) than both passive cooling in combination with gel packs (SD of 0.79) and active cooling (SD of 0.76). aEEG before TH was obtained in 35.8% of the infants and 86.5% had full EEG. One cUS was performed in 95.3% and MRI in 62.2% of the infants. Conclusion: Target temperature can be achieved with all three cooling methods. Passive cooling has the highest variation of temperature. Neuromonitoring should be improved in Swiss neonatal and paediatric intensive care units. Our results stress the importance of national registries.

Immune cell migration across the blood–brain barrier: molecular mechanisms and therapeutic targeting

The endothelial blood–brain barrier (BBB) and the epithelial blood–cerebrospinal fluid barrier protect the CNS from the constantly changing milieu within the bloodstream. The BBB strictly controls immune cell entry into the CNS, which is rare under physiological conditions. During a variety of pathological conditions of the CNS, such as viral or bacterial infections, or during inflammatory diseases, such as multiple sclerosis, immunocompetent cells readily traverse the BBB and subsequently enter the CNS parenchyma. Most of the available information on immune cell entry into the CNS is derived from studying experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Consequently, our current knowledge on traffic signals mediating immune cell entry across the BBB during immunosurveillance and disease results mainly from experimental data in the EAE model. Therefore, a large part of this review summarizes these findings. Similarly, the potential benefits and risks associated with therapeutic targeting of immune cell trafficking across the BBB will be discussed in the context of multiple sclerosis, since elucidation of the molecular mechanisms relevant to this disease have largely relied on the use of its in vivo model, EAE.

[Impact of tobacco use on the periodontium--an update. Part 2: Clinical and radiographic changes in the periodontium and effects on periodontal and implant therapy]

This third part of a series of publications from the Swiss task force "Smoking--Intervention in the private dental office" on the topic "tobacco use and dental medicine" describes the clinical and radiographic changes of the periodontium within smokers as well as the consequences of tobacco use on periodontal and implant therapy. With increased use of tobacco, patients show higher periodontal probing depths, increased clinical attachment loss, more alveolar bone resorption, a higher prevalence of gingival recessions, and a higher risk for tooth loss. In contrast to this, with smokers, the clinical characteristics of gingival inflammation or bleeding on periodontal probing are less established. Smokers show less positive results after conventional, surgical and regenerative periodontal therapy. The benefits of mucogingval surgery are reduced and less successful in smokers. Moreover, smoking impairs the osseointegration of oral implants and is at least partly responsible for a majority of biological complications in implant dentistry, such as periimplantitis. Based on the present understanding of periodontal diseases, the clinical findings, and the specific therapeutic outcomes with smokers, it appears to be reasonable, next to the current classification of periodontal diseases, to use the term "smokers periodontitis".

Use of ampicillin-sulbactam for treatment of experimental meningitis caused by a beta-lactamase-producing strain of Escherichia coli K-1

We evaluated the pharmacokinetics and therapeutic efficacy of ampicillin combined with sulbactam in a rabbit model of meningitis due to a beta-lactamase-producing strain of Escherichia coli K-1. Ceftriaxone was used as a comparison drug. The MIC and MBC were 32 and greater than 64 micrograms/ml (ampicillin), greater than 256 and greater than 256 micrograms/ml (sulbactam), 2.0 and 4.0 micrograms/ml (ampicillin-sulbactam [2:1 ratio, ampicillin concentration]) and 0.125 and 0.25 micrograms/ml (ceftriaxone). All antibiotics were given by intravenous bolus injection in a number of dosing regimens. Ampicillin and sulbactam achieved high concentrations in cerebrospinal fluid (CSF) with higher dose regimens, but only moderate bactericidal activity compared with that of ceftriaxone was obtained. CSF bacterial titers were reduced by 0.6 +/- 0.3 log10 CFU/ml/h with the highest ampicillin-sulbactam dose used (500 and 500 mg/kg of body weight, two doses). This was similar to the bactericidal activity achieved by low-dose ceftriaxone (10 mg/kg), while a higher ceftriaxone dose (100 mg/kg) produced a significant increase in bactericidal activity (1.1 +/- 0.4 log10 CFU/ml/h). It appears that ampicillin-sulbactam, despite favorable CSF pharmacokinetics in animals with meningitis, may be of limited value in the treatment of difficult-to-treat beta-lactamase-producing bacteria, against which the combination shows only moderate in vitro activity.

Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia

This study evaluated the efficacy and safety of intramuscular administration of NV1FGF, a plasmid-based angiogenic gene delivery system for local expression of fibroblast growth factor 1 (FGF-1), versus placebo, in patients with critical limb ischemia (CLI). In a double-blind, randomized, placebo-controlled, European, multinational study, 125 patients in whom revascularization was not considered to be a suitable option, presenting with nonhealing ulcer(s), were randomized to receive eight intramuscular injections of placebo or 2.5 ml of NV1FGF at 0.2 mg/ml on days 1, 15, 30, and 45 (total 16 mg: 4 x 4 mg). The primary end point was occurrence of complete healing of at least one ulcer in the treated limb at week 25. Secondary end points included ankle brachial index (ABI), amputation, and death. There were 107 patients eligible for evaluation. Improvements in ulcer healing were similar for use of NV1FGF (19.6%) and placebo (14.3%; P = 0.514). However, the use of NV1FGF significantly reduced (by twofold) the risk of all amputations [hazard ratio (HR) 0.498; P = 0.015] and major amputations (HR 0.371; P = 0.015). Furthermore, there was a trend for reduced risk of death with the use of NV1FGF (HR 0.460; P = 0.105). The adverse event incidence was high, and similar between the groups. In patients with CLI, plasmid-based NV1FGF gene transfer was well tolerated, and resulted in a significantly reduced risk of major amputation when compared with placebo.

Thermoregulatory management for mild therapeutic hypothermia

In recent years the use of mild therapeutic hypothermia as a means of neuroprotection has become an important concept for treatment after cerebral ischemic hypoxic injury. Mild therapeutic hypothermia has been shown to improve outcome after out-of-hospital cardiac arrest, and many studies suggest a beneficial effect of mild therapeutic hypothermia on patient outcome after traumatic brain injury, cerebrovascular damage and neonatal asphyxia. This review article explores the numerous possibilities and methods for the induction of mild therapeutic hypothermia, reviews thermoregulatory management during maintenance and discusses associated risks and complications.

Rituximab immunotherapy in pemphigus: therapeutic effects beyond B-cell depletion

The anti-CD20 mAb rituximab, first approved for use in B-cell malignancies, is increasingly used to treat a variety of autoimmune diseases. Two studies in this issue investigate the effects of rituximab in pemphigus. Rituximab induces not only a depletion of all B cells and a decline of antidesmoglein autoantibodies but also a decrease in desmoglein-specific T cells. Furthermore, B-cell populations recovered after treatment were modified. These novel aspects may contribute to the clinical responses observed in patients.

Resource use and outcome in critically ill patients with hematological malignancy: a retrospective cohort study

INTRODUCTION: The paucity of data on resource use in critically ill patients with hematological malignancy and on these patients' perceived poor outcome can lead to uncertainty over the extent to which intensive care treatment is appropriate. The aim of the present study was to assess the amount of intensive care resources needed for, and the effect of treatment of, hemato-oncological patients in the intensive care unit (ICU) in comparison with a nononcological patient population with a similar degree of organ dysfunction. METHODS: A retrospective cohort study of 101 ICU admissions of 84 consecutive hemato-oncological patients and 3,808 ICU admissions of 3,478 nononcological patients over a period of 4 years was performed. RESULTS: As assessed by Therapeutic Intervention Scoring System points, resource use was higher in hemato-oncological patients than in nononcological patients (median (interquartile range), 214 (102 to 642) versus 95 (54 to 224), P < 0.0001). Severity of disease at ICU admission was a less important predictor of ICU resource use than necessity for specific treatment modalities. Hemato-oncological patients and nononcological patients with similar admission Simplified Acute Physiology Score scores had the same ICU mortality. In hemato-oncological patients, improvement of organ function within the first 48 hours of the ICU stay was the best predictor of 28-day survival. CONCLUSION: The presence of a hemato-oncological disease per se is associated with higher ICU resource use, but not with increased mortality. If withdrawal of treatment is considered, this decision should not be based on admission parameters but rather on the evolutional changes in organ dysfunctions.

Cladophialophora bantiana: a rare cause of fungal brain abscess. Clinical aspects and new therapeutic options

Black molds or dematiaceous fungi are rare etiologic agents of intracerebral abscesses and such infections carry a high mortality of up to 70% despite combined surgical and antifungal therapy. While the growing use of immunosuppressive therapies and organ transplantation have caused an increase in the incidence of rare fungal cerebral infections, occurrence in immunocompetent hosts is also possible. We describe a 60-year-old female patient with a cerebral abscess caused by Cladophialophora bantiana. The case illustrates the clinical and radiological similarities between glioblastomas and brain abscesses and emphasizes the need to perform histological and microbiological studies prior to the initiation of any form of therapy. Long-term survival from cerebral black mold abscesses has been reported only when complete surgical resection was possible. The recommended antifungal treatment involves the use of amphotericin B combined with a triazole and, if possible, flucytosine. Highly-active new generation triazole antifungal compounds (voriconazole or posaconazole) are likely to offer improved survival rates for patients with rare mold infections. In particular, posaconazole could be a new therapeutic option given its better tolerance, lower toxicity and fewer drug-drug interactions. We discuss clinical, microbiological and practical pharmacological aspects and review current and evolving treatment options.

Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes

Cell death is essential for a plethora of physiological processes, and its deregulation characterizes numerous human diseases. Thus, the in-depth investigation of cell death and its mechanisms constitutes a formidable challenge for fundamental and applied biomedical research, and has tremendous implications for the development of novel therapeutic strategies. It is, therefore, of utmost importance to standardize the experimental procedures that identify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios. Thus far, dozens of methods have been proposed to quantify cell death-related parameters. However, no guidelines exist regarding their use and interpretation, and nobody has thoroughly annotated the experimental settings for which each of these techniques is most appropriate. Here, we provide a nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls. These guidelines are intended for investigators who study cell death, as well as for reviewers who need to constructively critique scientific reports that deal with cellular demise. Given the difficulties in determining the exact number of cells that have passed the point-of-no-return of the signaling cascades leading to cell death, we emphasize the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells.