Marginal Gap Formation in Approximal "Bulk Fill" Resin Composite Restorations After Artificial Ageing.

The aim of this in vitro study was to investigate the marginal gap formation of a packable "regular" resin composite (Filtek Supreme XTE [3M ESPE]) and two flowable "bulk fill" resin composites (Filtek Bulk Fill [3M ESPE] and SDR [DENTSPLY DeTrey]) along the approximal margins of Class II restorations. In each of 39 extracted human molars (n=13 per resin composite), mesial and distal Class II cavities were prepared, placing the gingival margins below the cemento-enamel junction. The cavities were restored with the adhesive system OptiBond FL (Kerr) and one of the three resin composites. After restoration, each molar was cut in half in the oro-vestibular direction between the two restorations, resulting in two specimens per molar. Polyvinylsiloxane impressions were taken and "baseline" replicas were produced. The specimens were then divided into two groups: At the beginning of each month over the course of six months' tap water storage (37°C), one specimen per molar was subjected to mechanical toothbrushing, whereas the other was subjected to thermocycling. After artificial ageing, "final" replicas were produced. Baseline and final replicas were examined under the scanning electron microscope (SEM), and the SEM micrographs were used to determine the percentage of marginal gap formation in enamel or dentin. Paramarginal gaps were registered. The percentages of marginal gap formation were statistically analyzed with a nonparametric analysis of variance followed by Wilcoxon-Mann-Whitney tests and Wilcoxon signed rank tests, and all p-values were corrected with the Bonferroni-Holm adjustment for multiple testing (significance level: α=0.05). Paramarginal gaps were analyzed descriptively. In enamel, significantly lower marginal gap formation was found for Filtek Supreme XTE compared to Filtek Bulk Fill ( p=0.0052) and SDR ( p=0.0289), with no significant difference between Filtek Bulk Fill and SDR ( p=0.4072). In dentin, significantly lower marginal gap formation was found for SDR compared to Filtek Supreme XTE ( p<0.0001) and Filtek Bulk Fill ( p=0.0015), with no significant difference between Filtek Supreme XTE and Filtek Bulk Fill ( p=0.4919). Marginal gap formation in dentin was significantly lower than in enamel ( p<0.0001). The percentage of restorations with paramarginal gaps varied between 0% and 85%, and for all three resin composites the percentages were markedly higher after artificial ageing. The results from this study suggest that in terms of marginal gap formation in enamel, packable resin composites may be superior to flowable "bulk fill" resin composites, while in dentin some flowable "bulk fill" resin composites may be superior to packable ones.

ESPEN guidelines on nutrition in cancer patients

Cancers are among the leading causes of morbidity and mortality worldwide, and the number of new cases is expected to rise significantly over the next decades. At the same time, all types of cancer treatment, such as surgery, radiation therapy, and pharmacological therapies are improving in sophistication, precision and in the power to target specific characteristics of individual cancers. Thus, while many cancers may still not be cured they may be converted to chronic diseases. All of these treatments, however, are impeded or precluded by the frequent development of malnutrition and metabolic derangements in cancer patients, induced by the tumor or by its treatment. These evidence-based guidelines were developed to translate current best evidence and expert opinion into recommendations for multi-disciplinary teams responsible for identification, prevention, and treatment of reversible elements of malnutrition in adult cancer patients. The guidelines were commissioned and financially supported by ESPEN and by the European Partnership for Action Against Cancer (EPAAC), an EU level initiative. Members of the guideline group were selected by ESPEN to include a range of professions and fields of expertise. We searched for meta-analyses, systematic reviews and comparative studies based on clinical questions according to the PICO format. The evidence was evaluated and merged to develop clinical recommendations using the GRADE method. Due to the deficits in the available evidence, relevant still open questions were listed and should be addressed by future studies. Malnutrition and a loss of muscle mass are frequent in cancer patients and have a negative effect on clinical outcome. They may be driven by inadequate food intake, decreased physical activity and catabolic metabolic derangements. To screen for, prevent, assess in detail, monitor and treat malnutrition standard operating procedures, responsibilities and a quality control process should be established at each institution involved in treating cancer patients. All cancer patients should be screened regularly for the risk or the presence of malnutrition. In all patients - with the exception of end of life care - energy and substrate requirements should be met by offering in a step-wise manner nutritional interventions from counseling to parenteral nutrition. However, benefits and risks of nutritional interventions have to be balanced with special consideration in patients with advanced disease. Nutritional care should always be accompanied by exercise training. To counter malnutrition in patients with advanced cancer there are few pharmacological agents and pharmaconutrients with only limited effects. Cancer survivors should engage in regular physical activity and adopt a prudent diet.

Physicochemical stability and compatibility testing of levetiracetam in all-in-one parenteral nutrition admixtures in daily practice.

BACKGROUND: Parenteral antiepileptic drugs are frequently used in critically ill patients for seizure control therapy or prevention. Many of these patients require additional parenteral nutrition (PN). Therefore, a parallel infusion of the frequently used antiepileptic drug levetiracetam (LEV) is interesting in terms of the restricted i.v. lines (e.g., neonates). The potential interactions of the complex PN admixture with the drug product and the appropriate admixing of a drug at effective dosages require physicochemical lab assessments to obtain specific and reliable pharmaceutical documentation for the intended admixing. AIM: To assess the of compatibility and stability of LEV, a neutral and hydrophilic drug, in commercial all-in-one (AiO) PN admixtures using simple validated tests to provide necessary data in a timely manner and to allow convenient, documented and safe treatment with PN as the drug vehicle. METHODS: Different concentrations of LEV were injected into two different AiO PN admixtures with no further additives. Stability and compatibility tests for the drug and the PN admixtures were performed over seven days at +4°C, +23±1°C and +37°C without light protection. Stability and sample characteristics were observed by visual inspection and the validated light microscope method. Moreover, the pH level of the admixture was checked, as were the concentrations of LEV over time in the PN admixtures, using an established LC-MS/MS method. RESULTS: The stability controls of LEV at different temperatures were within absolute ±20% of the theoretical value in a concentration range of 98.91-117.84% of the initial value. No changes in pH occurred (5.55±0.04) and no microscopic out of specification data or visual changes were observed. The mean value of the largest lipid droplet in each visual field over seven days was 2.4±0.08µm, comparable to that of the drug-free AiO admixture. Samples stored at +37°C showed yellowish discolorations after 96h of storage. CONCLUSION: LEV showed compatibility and stability over seven days in the selected PN admixtures, and the described methods represented a valuable and timely approach to determine the stability and compatibility of the highly hydrophilic, not dissociated LEV in AiO admixtures under conditions of use. Further studies with clinically relevant and representative examples of physicochemically different drug classes are needed.

Nutritional risk is a clinical predictor of postoperative mortality and morbidity in surgery for colorectal cancer.

BACKGROUND: This study investigated whether nutritional risk scores applied at hospital admission predict mortality and complications after colorectal cancer surgery. METHODS: Some 186 patients were studied prospectively. Clinical details, Reilly's Nutrition Risk Score (NRS) and Nutritional Risk Screening 2002 (NRS-2002) score, tumour stage and surgical procedure were recorded. RESULTS: The prevalence of patients at nutritional risk was 31.7 per cent according to Reilly's NRS and 39.3 per cent based on the NRS-2002. Such patients had a higher mortality rate than those not at risk according to Reilly's NRS (8 versus 1.6 per cent; P = 0.033), but not the NRS-2002 (7 versus 1.8 per cent; P = 0.085). Based on the NRS-2002, there was a significant difference in postoperative complication rate between patients at nutritional risk and those not at risk (62 versus 39.8 per cent; P = 0.004) but not if Reilly's NRS was used (58 versus 44.1 per cent; P = 0.086). Nutritional risk was identified as an independent predictor of postoperative complications (odds ratio 2.79; P = 0.002). CONCLUSION: Nutritional risk screening may be able to predict mortality and morbidity after surgery for colorectal cancer. However, the diverse results reflect either the imprecision of the tests or the small sample size.

[Myalgia and proximal muscle weakness in a young patient]. / Myalgien und proximale Muskelschwäche bei einer jungen Patientin.

We report a case of severe vitamin D-deficiency in a 32 year old black woman living in middle Europe since 9 years suffering from chronic pain of the lower back, the neck and the proximal right thigh, as well as weakness mainly in the pelvic girdle. Vitamin D plays an important role in calcium homeostasis and muscle strength. This case demonstrates that severe vitamin D-deficiency may be associated with musculoskeletal pain and weakness.

Neonatology/Paediatrics - Guidelines on Parenteral Nutrition, Chapter 13.

There are special challenges in implementing parenteral nutrition (PN) in paediatric patients, which arises from the wide range of patients, ranging from extremely premature infants up to teenagers weighing up to and over 100 kg, and their varying substrate requirements. Age and maturity-related changes of the metabolism and fluid and nutrient requirements must be taken into consideration along with the clinical situation during which PN is applied. The indication, the procedure as well as the intake of fluid and substrates are very different to that known in PN-practice in adult patients, e.g. the fluid, nutrient and energy needs of premature infants and newborns per kg body weight are markedly higher than of older paediatric and adult patients. Premature infants <35 weeks of pregnancy and most sick term infants usually require full or partial PN. In neonates the actual amount of PN administered must be calculated (not estimated). Enteral nutrition should be gradually introduced and should replace PN as quickly as possible in order to minimise any side-effects from exposure to PN. Inadequate substrate intake in early infancy can cause long-term detrimental effects in terms of metabolic programming of the risk of illness in later life. If energy and nutrient demands in children and adolescents cannot be met through enteral nutrition, partial or total PN should be considered within 7 days or less depending on the nutritional state and clinical conditions.

Practical handling of AIO admixtures - Guidelines on Parenteral Nutrition, Chapter 10.

All-in-one admixtures (AIO-admixtures) provide safe, effective and low-risk PN (parenteral nutrition) for practically all indications and applications. Water, energy (carbohydrates and lipids), amino acids, vitamins and trace elements are infused together with PN either as industrially-manufactured AIO admixtures provided as two- or three-chamber bags (shelf life usually more than 12 months) completed with electrolytes and micronutrients where appropriate or as individually compounded ready-to-use AIO admixtures (compounding, usually prepared by a pharmacy on either a daily or weekly basis and stored at 2-8 degrees C). Physico-chemical and microbial stability of an AIO admixture is essential for the safety and effectiveness of patient-specific PN, and its assurance requires specialist pharmaceutical knowledge. The stability should be documented for an application period of 24 (-48) hours. It is advisable to offer a limited selection of different PN regimes in each hospital. For reasons of drug and medication safety, PN admixtures prepared for individual patients must be correctly labelled and specifications for storage conditions must also be followed during transport. Monitoring is required where applicable. Micronutrients are usually administered separately to AIO admixtures. In case compatibility and stability have been well documented trace elements and/or combination preparations including water-soluble or water-soluble/fat soluble vitamin supplements can be added to PN admixtures under strict aseptic conditions. AIO admixtures are usually not used as vehicles for drugs (incompatibilities).

Kinetic assessment of persistent halogenated xenobiotics in cell culture models: comparison of mono- and poly-halogenated compounds.

We evaluated the suitability of single and multiple cell type cultures as model systems to characterise cellular kinetics of highly lipophilic compounds with potential ecotoxicological impact. Confluent mono-layers of human skin fibroblasts, rat astrocytoma C6 cells, non-differentiated and differentiated mouse 3T3 cells were kept in culture medium supplemented with 10% foetal calf serum. For competitive uptake experiments up to four different cell types, grown on glass sectors, were exposed for 3h to (14)C-labelled model compounds, dissolved either in organic solvents or incorporated into unilamellar lecithin liposomes. Bromo-, or chloro-benzenes, decabromodiphenylether (DBP), and dichlorodiphenyl ethylene (DDE) were tested in rather high concentration of 20 microM. Cellular toxicity was low. Compound levels were related to protein, DNA, and triglyceride contents. Cellular uptake was fast and dependent on physico-chemical properties of the compounds (lipophilicity, molecular size), formulation, and cell type. Mono-halogenated benzenes showed low and similar uptake levels (=low accumulation compounds). DBP and DDE showed much higher cellular accumulations (=high accumulation compounds) except for DBP in 3T3 cells. Uptake from liposomal formulations was mostly higher than if compounds were dissolved in organic solvents. The extent of uptake correlated with the cellular content of triglycerides, except for DBP. Uptake competition between different cell types was studied in a sectorial multi-cell culture model. For low accumulation compounds negligible differences were found among C6 cells and fibroblasts. Uptake of DDE was slightly and that of DBP highly increased in fibroblasts. Well-defined cell culture systems, especially the sectorial model, are appropriate to screen for bioaccumulation and cytotoxicity of (unknown) chemical entities in vitro.

Parenteral nutrition practices in hospital pharmacies in Switzerland, France, and Belgium.

OBJECTIVE: Important changes in administering total parenteral nutrition (PN) admixtures have occurred over the past decade. This study describes hospital pharmacists' practices in France (F), Switzerland (CH), and Belgium (B). METHODS: From the responses received using a standardized questionnaire, (n = 378) we determined the origin, types of container used, and choice of PN formula (standard versus tailor-made) and the type of quality control and the existence of nutrition support teams. RESULTS: The mean response rates were 55.6% (CH), 30.5% (F), and 24.5% (B). Standard formulas were used mainly for adult patients (CH, 86%; F, 79%; B, 86%), whereas approximately 50% of tailor-made PN bags were used for children. Single-compartment or multicompartment bags or glass bottles contained standard formulas. Most standard formulas were provided by industry, apart from (B), where 50% of PN solutions were compounded by hospital pharmacies. Single-compartment bags contained generally tailor-made formulas produced exclusively by hospital pharmacies in (CH) and (B), whereas 33% were provided by industry in (F). Quality controls were mostly visual and occurred in 75% to 95% of hospitals. Nutrition support teams were present in 32% to 45% of hospitals. CONCLUSION: The choice, origin, and type of container used for PN formulas were highly variable among countries. However, the use of standard formulas in bags was predominant in (CH) and (B). The function of nutrition support teams was similar in (F), (CH), and (B).

Rapid i.v. loading with phenytoin with subsequent dose adaptation using non-steady-state serum levels and a Bayesian forecasting computer program to predict maintenance doses.

OBJECTIVE: To evaluate the suitability of a phenytoin loading dose regimen; to assess whether dose-individualization was necessary and to investigate the reliability of a Bayesian forecasting method for phenytoin dose adaptation using non-steady-state levels in hospital-admitted patients. METHOD: An initial loading dose (15 mg phenytoin acid/kg BW) was given i.v. over 4 h, followed by standardized maintenance doses given i.v. in 12-h intervals from days 1 to 5 (175 mg 70 kg BW). The evening dose of day 5 was individualized based on three serum trough levels: L1 (after 16 h), L2 (morning day 4) and L3 (morning day 5). RESULTS: Ninety of 136 consecutive patients were evaluable in a prospective study for the standardized phase; 50 of them had additional serum levels in the individualized phase. There was no exclusion of patients with interacting co-medication. Seventy-seven per cent (L1) and 68% (L3) of patients showed therapeutic values (10-20 mg/L). The prediction error of the forecasting was 3.95 mg/L, the root mean squared error 6.27 mg/L (target trough level 11 mg/L). Seventy per cent of the levels (n=50) were within the 68% confidence interval. CONCLUSION: The effectiveness and safety of the regimen with rapid i.v. loading and the necessity to individualize phenytoin dosing after day 5 were demonstrated.

Prospective survey of parenteral nutrition in Switzerland: a three-year nation-wide survey.

BACKGROUND AND AIMS: The goals of this national survey were to determine the current PN practices and admixture formulations used in Switzerland. METHODS: During three years, an annual questionnaire was sent to all heads of Swiss hospital pharmacies. RESULTS: 92% of Swiss hospitals with a full-time pharmacist participated. Different PN systems were commonly used for adult patients: 2 commercial formulas in 2 or 3 compartments bags, 2 commercial formulas with/without lipid, 3 formulas compounded by the hospital pharmacy. For hospitalized adults, 83% of PN bags were administered as commercial multicompartment bags. The compounding of individualized PN admixtures takes place primarily in pharmacies of medium to large size hospitals. For pediatric PN, hospital compounding is routine because of individualized PN compositions and absence of commercially available standardized admixtures. Long-term home-PN was mostly delivered by hospital pharmacies (57%) or by private nutrition support home delivery services (37%). Most PN formula compositions complied with European guidelines and represented 2.6+/-2.0% of the hospital drug budget. Multi-disciplinary nutritional support teams were present in 52% of hospitals. CONCLUSION: In Switzerland, most PN for hospitalized adults were administered as commercial multi-compartment bags. The compounding of individualized PN admixtures were still important for pediatric patients and long-term home-PN.

Modulation of early growth response (EGR) transcription factor-dependent gene expression by using recombinant adenovirus.

Early growth response (EGR) transcription factors link initial cytoplasmic events to long-term alterations of cellular gene expression and are induced by various stimuli. To test their roles in cell physiology, we constructed adenoviral recombinants encoding NGFI-A binding protein 2 (NAB2, a repressor of EGR1, EGR2, and EGR3), EGR1, NAB-insensitive EGR1(I293F) (EGR1*), EGR2, and the NAB-binding, repressive domain 1 (R1) of EGR1. These viruses regulated EGR-dependent expression of GFP and luciferase reporter genes in heterologous expression assays. Infection of a myoblast cell line with EGR1 and EGR1* adenovirus induced the endogenous gene for platelet-derived growth factor A chain (PDGF-A). In addition, in neuroblastoma cells, the two novel EGR1 target genes EGR3 and NAB2 were identified by using adenoviral transfer of EGR1 and EGR1*. Our results demonstrate that recombinant adenovirus is useful to regulate heterologous and endogenous EGR target gene expression, and suggest that EGR transcription factors can autoregulate themselves.

Lipid peroxidation of intravenous lipid emulsions and all-in-one admixtures in total parenteral nutrition bags: the influence of trace elements.

An iodometric titration was used to assess the influence of a daily portion of trace elements on lipid peroxidation of pure lipid emulsions and lipid-containing all-in-one (AIO) admixtures by measuring the peroxide value (PV; mmol peroxides/L). A pure lipid emulsion (Intralipid 20%; Pharmacia & Upjohn, Dubendorf, Switzerland) was stored in ethylvinylacetate bags under light protection (LP) at 40 degrees C with and without trace elements. In absence of trace elements the PV of Intralipid 20% was significantly lower (day 14: 2.77 vs 18.04; p < .001). After the same time period with the same storage conditions the drop in pH was two times higher in presence of trace elements (1.54 vs 0.77). In an AIO admixture with LP stored at 2 degrees C to 8 degrees C, trace elements increased the PV from 0.04 to 0.19 mmol/L (day 29; p < .01). The drop in pH was 0.01 and 0.02 units, respectively. When stored at 20 degrees C to 30 degrees C and exposed to daylight, the PV of the AIO admixture containing trace elements reached 1.92 compared with 0.52 in their absence (day 19; p < .001) with a pH drop of 0.03 and 0.11, respectively (day 29). Although trace elements led to a much higher drop in pH in pure lipid emulsions, no obvious influence on the pH of AIO admixtures was demonstrated. To minimize lipid peroxidation, AIO admixtures should be stored light-protected and refrigerated without trace elements. The latter should be added immediately before administration or should be given separately.

Lipid peroxidation of i.v. lipid emulsions in TPN bags: the influence of tocopherols.

Four commercial i.v. lipid emulsions containing soybean oil were investigated to determine the tocopherol content. A sensitive high-performance liquid chromatography (HPLC) on a diol column was established to quantitate the tocopherol isomers in lipid emulsions. A previously described iodometric titration was used to assess the peroxide value (mmol peroxides/L). The pH was measured also. The initial tocopherol concentration ranges in three of the four commercial soybean oil-based 20% lipid emulsions studied were compared ([mg/L]: alpha: 17-23, beta: 4, gamma: 88-129, delta: 40-44). One product showed an increased alpha-tocopherol content (172 mg/L) due to supplementation during manufacture. During storage in an ethylvinyl acetate (EVA) bag at 40 degrees C under light-protection (LP) for 34 d, a lipid emulsion 20% with a natural alpha-tocopherol content showed a peroxide value (PV) of 9.18 (about 450 times the value of controls in glass bottles) with a concomittant reduction of the tocopherol isomers to 61.6% (alpha), 86.5% (gamma), and 88.9% (delta) compared to the initial values. Comparison of two lipid emulsions with different amounts of alpha-tocopherol (Lipidem 20%, B. Braun, Switzerland: 156.29 mg/L vs. Intralipid 20%, Pharmacia Upjohn, Switzerland: 8.75 mg/L) for their antioxidative capacity using the same stress conditions revealed for the emulsion with the high alpha-tocopherol content a significantly higher PV over the whole test period (after 5 wk: 33.63 vs. 6.23; P < 0.001) and an increased alpha-tocopherol decomposition (51.6% vs. 8.7%). The drop in pH was higher, also (1.9 vs. 1.0 pH units). In contrast to ordinary concentrations of about 20 mg/L, alpha-tocopherol in 20% lipid emulsions showing antioxidative properties, a supplementation with about 160 mg/L showed a prooxidative effect when exposed to ambient atmosphere in an EVA bag.

A PDGF-regulated immediate early gene response initiates neuronal differentiation in ventricular zone progenitor cells.

When exposed to platelet-derived growth factor (PDGF), uncommitted neuroepithelial cells from the developing cortex of embryonic day 14 (E14) rats develop into neurons. Outward signs of the neuronal phenotype are not observed for 4 days following exposure to PDGF. However, only a brief (2-3 hr) period of PDGF receptor activation is required to initiate neuronal development. During the window of receptor activation, RNA synthesis is essential, but protein synthesis is not. These observations indicate that specification of neuronal fate is mediated by an immediate early gene response.

In vitro oxidation of i.v. lipid emulsions in different all-in-one admixture bags assessed by an iodometric assay and gas-liquid chromatography.

Polyunsaturated fatty acids (FAs) of intravenous (IV) lipid emulsions can peroxidize to potentially harmful lipid hydroperoxides. In order to assess in vitro peroxidation of IV fat emulsions in all-in-one (AIO) admixture bags, an iodometric titration to determine lipid hydroperoxide content expressed by the peroxide value (PV) and a gas-liquid chromatographic (GLC) assay to determine changes of the FA pattern were established. A long-chain triglyceride (LCT) and medium-chain triglyceride-LCT emulsion were compared for the PV and the pH during storage at room temperature and daylight in AIO bags made of ethylvinylacetate (EVA) and polypropylene:polyamide 7:3 (V90). In contrast to storage in glass bottles, significant peroxidation was detected in both emulsions with 0.5-3.4 mmol peroxides/L after 28 d (150 times the control PV). A pH drop of at least 0.3 (EVA) and 1.2 (V90) units was measured. Initial PVs and peroxidation kinetics of the emulsions were different; V90 material showed better barrier properties against oxygen. PV was increased by higher temperature and light exposure. The FA pattern of an LCT emulsion with a PV > 6 (storage: 40 degrees C in a dark room for 28 d in AIO bags) assayed by GLC remained unchanged. The iodometric peroxide and the GLC assay were reproducible and easy to handle. Only the iodometric method was sensitive enough to detect peroxidation effects (detection limit: 0.02 mmol peroxides/L). IV fat emulsions can be checked for lipid hydroperoxide content with the rapid iodometric assay to guarantee optimal quality of IV lipids used for AIO admixtures. To prevent peroxidation, lipids in AIO bags should be stored light-protected in a refrigerator an oxygen-tight overwrap is mandatory for extended periods.

[Successful therapy of salicylate poisoning using glycine and activated charcoal]. / Erfolgreiche Therapie akuter Salizylatintoxikationen mit Glycin und Aktivkohle.

Acute intoxications with salicylates are common. In a dosage of 150-300 mg/kg they are severe, and above 500 mg/kg potentially fatal. To commit suicide 4 patients ingested 375-460 mg/kg acetylsalicylic acid; 3-8 hours after ingestion salicylate blood levels of up to 760 mg/l were observed. The patients were treated for a period of 16 hours with oral charcoal and glycine (1 g/kg initially, followed every 4 hours by 0.5 g/kg, and 8 g initially, followed by 4 g, respectively). To increase urinary pH (7-9) they received i.v. NaHCO3. Blood levels of salicylic acid including its metabolites dropped initially with a virtual half-life of 2-4 hours. 18 hours after hospital admission every patient was in good general condition; none of them required hemodialysis. The urinary excretion of total salicylate reached only 6-14% of the dose within the first 12 hours of therapy, clearly indicating the importance of combined therapy with glycine and charcoal in achieving a good clinical outcome.