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Background: Every physician has a unique professional identity. However, little is known about the diversity of identities among physicians. This study aimed to quantitatively assess the professional identity of physicians in Finland using descriptions of professional identity., Methods: This study was part of a larger cross-sectional Finnish Physician 2018 Study. The target population consisted of all Finnish physicians under the age of 70 (N = 24,827) in 2018. The sample was drawn from physicians born on even numbered days (N = 11,336) using the Finnish Medical Association register. A total of 5,187 (46%) physicians responded. Professional identity was examined by 27 given characterisations using a five-point Likert scale. Multivariate logistic regression was used in assessing how place of work, graduation year and gender were associated with identity descriptions., Results: The descriptions which most physicians identified with were "member of a working group/team" (82%), "helper" (82%), and "health expert" (79%); the majority reported these as describing them very or quite well. Identity descriptions such as "prescriber of medications" (68% vs. 45%), "prioritiser" (57% vs. 35%) and "someone issuing certificates" (52% vs. 32%) were more popular among junior than senior physicians. The biggest differences between the genders were found in the descriptions "provider of comfort" (62% vs. 40%) and "someone engaged in social work" (45% vs. 25%), with which women identified more frequently than men., Conclusions: Strong identification as a member of a team is an important finding in the increasingly multiprofessional world of health care. Importantly, most physicians shared several core professional identity descriptions (i.e., helper, health expert) that reflect the traditional image of an exemplary doctor., (© 2024. The Author(s).)

In theoretical physics and theoretical neuroscience, increased intelligence is associated with increased entropy, which entails potential access to an increased number of states that could facilitate adaptive behavior. Potential to access a larger number of states is a latent entropy as it refers to the number of states that could possibly be accessed, and it is also recognized that functioning needs to be efficient through minimization of manifest entropy. For example, in theoretical physics, the importance of efficiency is recognized through the observation that nature is thrifty in all its actions and through the principle of least action. In this paper, system intelligence is explained as capability to maintain internal stability while adapting to changing environments by minimizing manifest task entropy while maximizing latent system entropy. In addition, it is explained how automated negotiation relates to balancing adaptability and stability; and a mathematical negotiation model is presented that enables balancing of latent system entropy and manifest task entropy in intelligent systems. Furthermore, this first principles analysis of system intelligence is related to everyday challenges in production systems through multiple simulations of the negotiation model. The results indicate that manifest task entropy is minimized when maximization of latent system entropy is used as the criterion for task allocation in the simulated production scenarios.

Objective: High-density lipoprotein (HDL) is a heterogeneous group of subpopulations differing in protein/lipid composition and in their anti-atherogenic function. There is a lack of assays that can target the functionality of HDL particles related to atherosclerosis. The objective of this study was to construct two-site apolipoprotein A-I (apoA-I) assays and to evaluate their clinical performance in patients with suspected obstructive coronary artery disease (CAD)., Approach and Results: Direct two-site apoA-I assays (named 109-121 and 110-525) were developed to identify the presence of apoA-I in the HDL of patients with CAD using apoA-I antibodies as a single-chain variable fragment fused with alkaline phosphatase. ApoA-I 109-121 and apoA-I 110-525 were measured in 197 patients undergoing coronary computed tomography angiography (CTA) and myocardial positron emission tomography perfusion imaging due to suspected obstructive CAD. Among patients not using lipid-lowering medication (LLM, n = 125), the level of apoA-I 110-525 was higher in the presence than in the absence of coronary atherosclerosis [21.88 (15.89-27.44) mg/dl vs. 17.66 (13.38-24.48) mg/dl, P = 0.01)], whereas there was no difference in apoA-I 109-121 , HDL cholesterol, and apoA-I determined using a polyclonal apoA-I antibody. The levels of apoA-I 109-121 and apoA-I 110-525 were similar in the presence or absence of obstructive CAD. Among patients not using LLM, apoA-I 110-525 adjusted for age and sex identified individuals with coronary atherosclerosis with a similar accuracy to traditional risk factors [area under the curve [AUC] (95% CI): 0.75(0.66-0.84) 0.71 (0.62-0.81)]. However, a combination of apoA-I 110-525 with risk factors did not improve the accuracy [AUC (95% CI): 0.73 (0.64-0.82)]., Conclusion: Direct two-site apoA-I assays recognizing heterogeneity in reactivity with apoA-I could provide a potential approach to identify individuals at a risk of coronary atherosclerosis. However, their clinical value remains to be studied in larger cohorts., Competing Interests: Author AS declares fees for lectures or consultancy from Abbott, Amgen, Astra Zeneca (AS and JK), Boehringer Ingelheim, Bayer and Pfizer, Novartis (JK), GE Healthcare (JK). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Negi, Heikkilä, Vuorenpää, Tuunainen, Nammas, Maaniitty, Knuuti, Metso, Lövgren, Jauhiainen, Lamminmäki, Pettersson and Saraste.)

Measurement of cardiac troponin I (cTnI) should be feasible for point-of-care testing (POCT) to diagnose acute myocardial infarction (AMI). Lateral flow immunoassays (LFIAs) have been long implemented in POCT and clinical settings. However, sensitivity, matrix effect and quantitation in lateral flow immunoassays (LFIAs) have been major limiting factors. The performance of LFIAs can be improved with upconverting nanoparticle (UCNP) reporters. Here we report a new methodological approach to quantify cTnI using UCNP-LFIA technology with minimized plasma interference. The performance of the developed UCNP-LFIA was evaluated using clinical plasma samples (n = 262). The developed UCNP-LFIA was compared to two reference assays, the Siemens Advia Centaur assay and an in-house well-based cTnI assay. By introducing an anti-IgM scrub line and dried EDTA in the LFIA strip, the detection of cTnI in plasma samples was fully recovered. The UCNP-LFIA was able to quantify cTnI concentrations in patient samples within the range of 30-10,000 ng/L. The LoB and LoD of the UCNP-LFIA were 8.4 ng/L and 30 ng/L. The method comparisons showed good correlation (Spearman's correlation 0.956 and 0.949, p < 0.0001). The developed UCNP-LFIA had LoD suitable for ruling in AMI in patients with elevated cTnI levels and was able to quantify cTnI concentrations in patient samples. The technology has potential to provide simple and rapid assay for POCT in ED setting., (© 2021. The Author(s).)

Objective: The volume of research work done by general practitioners (GP) is modest compared to other specialties. In order to find out reasons for this we examined the current situation concerning research orientation and factors relating to them among Finnish GPs compared to other specialists., Design and Setting: Data from The Physician 2018 Study were used for our research. The study was undertaken in collaboration with all five medical faculties in Finland and the Finnish Medical Association. It compiled information on physicians` social background, work history and career and research plans as well as their views regarding undergraduate and specialist training, values, and professional identity., Subjects: The basic study population comprised all Finnish doctors under 70 years of age ( N  = 23,131). Questionnaires were sent to doctors born on even-numbered days ( n  = 11,336). Altogether 5,214 (45.8%) responded. Responses from GPs ( n  = 796) were compared with those of doctors in other specialties ( n  = 3,514)., Main Outcome Measures and Results: The respondents were asked about their current intention to undertake a doctoral degree. Factors associated with this were analysed. Only 7.3% of GPs had completed a doctoral degree. The corresponding figure in other specialties was 32.3% ( p  < 0.001). In general practice the current intention to undertake a doctoral degree had only slightly increased over ten years. Most GPs had also decided not to undertake a doctorate. The main factors associated with the current intention to complete a doctoral degree were interest in attaining a senior position (OR 3.43, 95% CI 2.25-5.24), a position in a university hospital district (OR 2.89, 95% CI 1.69-4.94) or other sector than primary care (OR 1.87, 95% CI 1.18-2.96), one's father being a doctor (OR 2.01, 95% CI 1.09-3.72) and male gender (OR 1.63, 95% CI 1.05-2.54)., Conclusion: Research work in primary health care has been quite sparse. In general practice there is a need to increase teaching and guidance in research work.Key pointsResearch work in primary health care is not very common.Only 7.3% of GPs had completed their doctorate compared to 32.3% in other specialties.A main factor associated with the current intention to complete a doctoral degree was interest in attaining a senior position.

High density lipoproteins (HDL) are a heterogenous group of subpopulations differing in protein/lipid composition and in their anti-atherogenic function. There is a lack of specific and robust assays which can target the functionality of HDL with respect to atherosclerosis. With recently generated CAD HDL targeted, single chain recombinant antibodies (scFvs) we set out to design and optimize apo A-I tests to compare it with conventional HDL-C and apo A-I analyses for diagnosis and risk assessment of coronary artery disease (CAD) and its outcome. Three highly sensitive two-site apo A-I assays: 022-454, 109-121 and 110-525 were optimized. A preliminary clinical evaluation of these assays, after proper sample dilution procedure, was performed using samples derived from 195 chest pain patients (myocardial infarction (MI), n = 86 and non-MI, n = 109), collected at the time of admission and at discharge from hospital (hospital stay ≤ 24 h). The clinical performance of the assays was compared with apo A-I measured with polyclonal anti-apo A-I antibody using conventional ELISA. Apo A-I data was in addition compared with HDL-C concentration of the samples. The concentration of apo A-I was significantly lower in MI patients than in non-MI individuals with assay 022-454 (admission and discharge samples, P < 0.0001 and = 0.004); assay 109-121 (admission and discharge samples, P = 0.04 and 0.0009), and, ELISA based apo A-I test (admission and discharge samples, P = 0.008 and < 0.0001). HDL-C (admission and discharge samples, P = 0.002 and P = 0.01) was also significantly lower in MI patients. In Kaplan- Meier analysis, two-site assay 109-121 assay predicted mortality from admission samples at 1.5 yrs (whole cohort, P = 0.01 and in MI patients, P = 0.05) and at 6 months (whole cohort, P = 0.04). Assay 110-525 predicted mortality at 1.5 yrs from admission samples of non-MI patients (P = 0.01) and at 6 months from whole discharge sample cohort (P = 0.04). Polyclonal anti-apo A-I based conventional assay predicted mortality at 1.5 yrs from admission samples of whole cohort (P = 0.03). Two-site apo A-I assay 022-454 and HDL-C provided no capability of predicting mortality in the whole cohort or any sub-group. In conclusion, two of the tested recombinant apo A-I antibody combinations (sc 109-121 and sc 110-525) display promising outcome to improve diagnosis and prediction of future cardiac events in cardiac patients over polyclonal apo A-I ELISA and HDL-C assays. The noted differences, while interesting, are preliminary and need however to be verified in extensive cohorts of pathological cardiac conditions and healthy controls., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Keratin intermediate filament proteins are major cytoskeletal components of the mammalian simple layered columnar epithelium in the gastrointestinal tract. Human colon crypt epithelial cells express keratins 18, 19 and 20 as the major type I keratins, and keratin 8 as the type II keratin. Keratin expression patterns vary between species, and mouse colonocytes express keratin 7 as a second type II keratin. Colonic keratin patterns change during cell differentiation, such that K20 increases in the more differentiated crypt cells closer to the central lumen. Keratins provide a structural and mechanical scaffold to support cellular stability, integrity and stress protection in this rapidly regenerating tissue. They participate in central colonocyte processes including barrier function, ion transport, differentiation, proliferation and inflammatory signaling. The cell-specific keratin compositions in different epithelial tissues has allowed for the utilization of keratin-based diagnostic methods. Since the keratin expression pattern in tumors often resembles that in the primary tissue, it can be used to recognize metastases of colonic origin. This review focuses on recent findings on the biological functions of mammalian colon epithelial keratins obtained from pivotal in vivo models. We also discuss the diagnostic value of keratins in chronic colonic disease and known keratin alterations in colon pathologies. This review describes the biochemical properties of keratins and their molecular actions in colonic epithelial cells and highlights diagnostic data in colorectal cancer and inflammatory bowel disease patients, which may facilitate the recognition of disease subtypes and the establishment of personal therapies in the future., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The construction industry is regarded as one of the most unsafe occupational fields worldwide. Despite general agreement that safety training is an important factor in preventing accidents in the construction sector, more studies are needed to identify effective training methods. To address the current research gap, this study evaluated the impact of novel, participatory safety training methods on construction workers' safety competencies. Specifically, we assessed the efficacy of an immersive virtual reality (VR)-based safety training program and a participatory human factors safety training program (HFST) in construction industry workplaces., Method: In 2019, 119 construction sector workers from eight workplaces participated in a randomized controlled trial conducted in Finland. All the study participants were assessed using questionnaires at baseline, immediately after the intervention and at one-month follow-up. We applied generalized linear mixed modeling for statistical analysis., Results: Compared to lecture-based safety training, VR-based safety training showed a stronger impact on safety motivation, self-efficacy and safety-related outcome expectancies. In addition, the construction sector workers who participated in the VR-based safety training showed a greater increase in self-reported safety performance at one-month follow-up. Contrary to our study hypotheses, we found no significant differences between the study outcomes in terms of study participants in the HFST training condition and the comparison condition without HFST training., Conclusion: Our study indicates that VR technology as a safety training tool has potential to increase safety competencies and foster motivational change in terms of the safety performance of construction sector workers. In the future, the efficacy of participatory human factors safety training should be studied further using a version that targets both managerial and employee levels and is implemented in a longer format., Practical Implications: Safety training in virtual reality provides a promising alternative to passive learning methods. Its motivating effect complements other safety training activities., (Copyright © 2020. Published by Elsevier Ltd.)

Tidal disruption events (TDEs) are transient flares produced when a star is ripped apart by the gravitational field of a supermassive black hole (SMBH). We have observed a transient source in the western nucleus of the merging galaxy pair Arp 299 that radiated >1.5 × 10 52 erg at infrared and radio wavelengths but was not luminous at optical or x-ray wavelengths. We interpret this as a TDE with much of its emission reradiated at infrared wavelengths by dust. Efficient reprocessing by dense gas and dust may explain the difference between theoretical predictions and observed luminosities of TDEs. The radio observations resolve an expanding and decelerating jet, probing the jet formation and evolution around a SMBH., (Copyright © 2018, American Association for the Advancement of Science.)

Feeding pets raw meat-based diets (RMBDs) is commonly practiced by many companion animal owners and has received increasing attention in recent years. It may be beneficial for the animals, but may also pose a health risk for both pets and their owners, as RMBDs may be contaminated by enteric pathogens-such as Campylobacter, Salmonella, and Yersinia-which are the most common zoonotic bacteria causing enteritis in humans. Little information exists on the prevalence of these pathogens in pet food, and thus one aim was to investigate the prevalence of Campylobacter, Salmonella, and Yersinia in commercial RMBDs from retail stores. Little evidence also exists on the significance of raw meat feeding on the shedding of Campylobacter, Salmonella, and enteropathogenic Yersinia in the feces of pets, and therefore, the second goal was to study the presence of these pathogens in dogs and cats fed RMBDs. Polymerase chain reaction (PCR) only sporadically detected Campylobacter, Salmonella, and enteropathogenic Yersinia in RMBDs. These pathogens were not found by culturing, indicating a low contamination level in frozen RMBDs. They were also detected in the feces of dogs and cats, but the association with feeding RMBDs to them remained unclear.

Forage type and management influences the nutritional quality and fatty acid composition of ruminant milk. Replacing grass silage with red clover (RC; L.) silage increases milk fat 18:3-3 concentration. Red clover has a higher polyphenol oxidase (PPO) activity compared with grasses, which has been suggested to decrease lipolysis and . The present study characterized the abundance and fatty acid composition of esterified lipid and NEFA before and after ensiling of grass and RC to investigate the influence of forage species, growth stage, and extent of fermentation on lipolysis. A randomized block design with a 2 × 3 × 4 factorial arrangement of treatments was used. Treatments comprised RC or a mixture of timothy ( L.) and meadow fescue ( Huds.) harvested at 3 growth stages and treated with 4 levels of formic acid (0, 2, 4, and 6 L/t). Lipid in silages treated with 0 or 6 L/t formic acid were extracted and separated into 4 fractions by TLC. Total PPO activity in fresh herbage and the content of soluble bound phenols in all silages were determined. Concentrations of 18:3-3 and total fatty acids (TFA) were higher ( < 0.001) for RC than for grass. For both forage species, 18:3-3 and TFA content decreased linearly ( < 0.001) with advancing growth stage, with the highest abundance at the vegetative stage. Most of lipid in fresh RC and grass herbage (97%) was esterified, whereas NEFA accounted for 71% of TFA in both silages. Ensiling resulted in marginal increases in TFA content and the amounts of individual fatty acids compared with fresh herbages. Herbage total PPO activity was higher ( < 0.001) for RC than grass (11 vs. 0.11 μkatal/g leaf fresh weight). Net lipolysis during ensiling was extensive for both forage species (660 to 759 g/kg fatty acid for grass and 563 to 737 g/kg fatty acid for RC). Formic acid application (0 vs. 6 L/t) resulted in a marked decrease ( = 0.026) in net lipolysis during the ensiling of RC, whereas the opposite was true ( = 0.026) for grass. In conclusion, results suggest that formic acid addition during the ensilage of RC decreases lipolysis . For both plant species, total PPO activity was not associated with the extent of lipolysis . However, bound phenols formed via PPO activity appear to have a role in protecting lipid and protein against degradation in grass and lowering proteolysis of RC during ensiling.

Objectives: To study the skeletal troponin I (skTnI) cross-reactivity of four different commercially available antibodies in four cardiac troponin I (cTnI) research assay versions having the same epitope specificity as evidenced by peptide mapping., Design and Methods: The four research assays all use two solid phase antibodies and one detection antibody attached to intrinsically fluorescent nanoparticles. Two alternative antibodies were used for one capture antibody and two for the detector antibody. The assays were evaluated in terms of analytical sensitivity and by determining assay cross-reactivity to skTnI. Additionally, regression analysis was performed by measuring a sample panel (n=101) with all of the four assay versions., Results: A false-positive cTnI concentration of >7000ng/L was measured with one of the assay versions, when serum was spiked with 500,000ng/L skTnI. The corresponding observed cTnI values for the other three assay versions varied from 616ng/L to 727ng/L. Out of the 101 clinical samples assayed, five showed spuriously (3- to 148-fold) elevated cTnI values with the skTnI interference prone assay setup, but not with the other assay versions. According to our investigational skTnI assay, all five samples contained measurable amounts of skTnI (range: 5500-702,000ng/L)., Conclusions: Two out of four cTnI antibodies tested cross-reacted vastly with skTnI but did not cause any notable interference unless paired together. Therefore, skTnI cross-reactivity should be carefully assessed when cTnI assay antibodies claimed to be cTnI specific are selected., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: To introduce a novel nanoparticle-based immunoassay for cardiac troponin I (cTnI) utilizing chimeric antibody fragments and to demonstrate that removal of antibody Fc-part and antibody chimerization decrease matrix related interferences., Design and Methods: A sandwich-type immunoassay for cTnI based on recombinant chimeric (mouse variable/human constant) antigen binding (cFab) antibodies and intrinsically fluorescent nanoparticles was developed. To test whether using chimeric antibody fragments helps to avoid matrix related interferences, samples (n=39) with known amounts of triglycerides, bilirubin, rheumatoid factor (RF) or human anti-mouse antibodies (HAMAs) were measured with the novel assay, along with a previously published nanoparticle-based research assay with the same antibody epitopes., Results: The limit of detection (LoD) was 3.30ng/L. Within-laboratory precision for 29ng/L and 2819ng/L cTnI were 13.7% and 15.9%, respectively. Regression analysis with Siemens ADVIA Centaur® yielded a slope (95% confidence intervals) of 0.18 (0.17-1.19) and a y-intercept of 1.94 (-1.28-3.91) ng/L. When compared to a previously published nanoparticle-based assay, the novel assay showed substantially reduced interference in the tested interference prone samples, 15.4 vs. 51.3%. A rheumatoid factor containing sample was decreased from 241ng/L to

In Finland, achieving licensure as a specialist in general practice takes six years, with four years of training in primary care. Usually training arrangements are evaluated by trainees and their trainers. In this study the opinions of licensed GPs with experience of working in practice were specifically addressed. Our aim was to evaluate Finnish general practitioners' satisfaction with their specialty training and with the training programme. Correlations between these evaluations were investigated using logistic regression analyses. Participants comprised 416 GPs and 131 GP trainees, who responded to the Finnish Physician 2008 Study (response rate 53.7%). The respondents were asked how satisfied they were with their own specialty training in general, how satisfied they were with 12 items in their specialty training programme, and how well specialty training matched the requirements of GP work. Two-thirds of GPs and GP trainees were satisfied with their specialty training. Almost three in four felt that GP training succeeded in matching the requirements of work in general practice. Good ratings of diagnostic skill learning during GP training were predictive of overall training satisfaction. Clinical training relevant to GP work is the key element in ensuring satisfaction with general practice specialty training. The views of qualified GPs with experience gained in work provide a valuable addition to the total transformational quality management of GP training.

Background: The competencies required of a GP are complex and ever-expanding. GP training should adequately cover all the content areas., Objectives: The aim was to assess GPs' and GP trainees' satisfaction with their specialist training and with the contents of training. Trends in assessments over a ten-year period were investigated., Methods: Data from Finnish national surveys of physicians conducted in 1998, 2003 and 2008 were analysed with 606, 457 and 324 GPs and GP trainees respectively being sampled in the present study. Respondents were asked how satisfied they were with their own specialist training in general, and how much instruction they had received in 12 specific areas during their specialist training., Results: Satisfaction with GP training slowly increased during the study years. In 2008, 59% of respondents were satisfied with their training, compared to 46% in 1998. The best covered content area was clinical work. Major shortcomings were reported in many of the content areas analysed, e.g. management and leadership., Conclusion: Although the trend in satisfaction with GP training in Finland is for the better, there are shortcomings, especially in many of the non-clinical content areas of training. More attention needs to be paid to these areas in the future.

Diets based on red clover silage (RCS) typically increase the concentration of polyunsaturated fatty acids (PUFA) in ruminant meat and milk and lower the efficiency of N utilization compared with grass silages (GS). Four multiparous Finnish Ayrshire cows (108 d postpartum) fitted with rumen cannulas were used in a 4 × 4 Latin square design with 21-d periods to evaluate the effect of incremental replacement of GS with RCS on milk production, nutrient digestion, whole-body N metabolism, and milk fatty acid composition. Treatments comprised total mixed rations offered ad libitum, containing 600 g of forage/kg of diet dry matter (DM), with RCS replacing GS in ratios of 0:100, 33:67, 67:33, and 100:0 on a DM basis. Intake of DM and milk yield tended to be higher when RCS and GS were offered as a mixture than when fed alone. Forage species had no influence on the concentration or secretion of total milk fat, whereas replacing GS with RCS tended to decrease milk protein concentration and yield. Substitution of GS with RCS decreased linearly whole-tract apparent organic matter, fiber, and N digestion. Forage species had no effect on total nonammonia N at the omasum, whereas the flow of most AA at the omasum was higher for diets based on a mixture of forages. Replacing GS with RCS progressively lowered protein degradation in the rumen, increased linearly ruminal escape of dietary protein, and decreased linearly microbial protein synthesis. Incremental inclusion of RCS in the diet tended to lower whole-body N balance, increased linearly the proportion of dietary N excreted in feces and urine, and decreased linearly the utilization of dietary N for milk protein synthesis. Furthermore, replacing GS with RCS decreased linearly milk fat 4:0 to 8:0, 14:0, and 16:0 concentrations and increased linearly 18:2n-6 and 18:3n-3 concentrations, in the absence of changes in cis-9 18:1, cis-9, trans-11 18:2, or total trans fatty acid concentration. Inclusion of RCS in the diet progressively increased the apparent transfer of 18-carbon PUFA from the diet into milk, but had no effect on the amount of 18:2n-6 or 18:3n-3 at the omasum recovered in milk. In conclusion, forage species modified ruminal N metabolism, the flow of AA at the omasum, and whole-body N partitioning. A lower efficiency of N utilization for milk protein synthesis with RCS relative to GS was associated with decreased availability of AA for absorption, with some evidence of an imbalance in the supply of AA relative to requirements. Higher enrichment of PUFA in milk for diets based on RCS was related to an increased supply for absorption, with no indication that forage species substantially altered PUFA bioavailability., (Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Diets based on red clover silage (RCS) typically increase the concentration of polyunsaturated fatty acids (PUFA) in ruminant milk and meat compared with grass silages (GS), an effect that has been attributed to higher activity of polyphenol oxidase in red clover, promoting ruminal escape of dietary lipid. Four multiparous Finnish Ayrshire cows in mid lactation fitted with rumen cannulas were used in a 4×4 Latin Square design with 21-d experimental periods to evaluate the effects of incremental replacement of GS with RCS on ruminal lipid metabolism, using the omasal sampling technique in combination with Cr-EDTA, Yb acetate, and indigestible neutral detergent fiber as markers. Treatments comprised total mixed rations offered ad libitum containing 600 g of forage/kg of diet dry matter, with RCS replacing GS in a ratio of 0:100, 33:67, 67:33, and 100:0 on a dry matter basis. Silages contained a high proportion of lipid as nonesterified fatty acids (NEFA), with no difference between forage species (75 and 73% for GS and RCS, respectively). Substitution of GS with RCS had no influence on the intakes of NEFA, polar lipid, triacylglycerol, diacylglycerol, monoacylglycerol, or total fatty acids (FA), but altered the ingestion of specific FA. Replacing GS with RCS decreased linearly 18:3n-3 and increased linearly 18:2n-6 intakes. Changes in the proportion of RCS in the diet had no effect on the amounts or on the relative proportions of different lipid fractions at the omasum. On average, NEFA, polar lipid, triacylglycerol, diacylglycerol, and monoacylglycerol accounted for 80, 12, 4.4, 2.4, and 0.8% of total FA in omasal digesta, respectively. Replacement of GS with RCS increased linearly the amount of esterified and nonesterified 18:3n-3 at the omasum. Flows of cis-9 18:1 and 18:2n-6 were also increased linearly in response to RCS in the diet, whereas 3,7,11,15-tetramethyl-16:0 at the omasum was decreased. Replacing GS with RCS in the diet decreased linearly the lipolysis of dietary esterified lipids in the rumen from 85 to 70%. Effects on lipolysis due to forage species were also associated with linear decreases in apparent ruminal 18:3n-3 biohydrogenation from 93 to 85% and a trend toward lowered biohydrogenation of cis-9 18:1 and 18:2n-6 in the rumen. However, forage species had no effect on the flow of bound phenols formed as a consequence of polyphenol oxidase activity at the omasum. In conclusion, despite minimal differences in the extent of lipolysis in silo, lipid and constituent FA in RCS were less susceptible to ruminal lipolysis and biohydrogenation compared with GS., (Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Sink conditions used in dissolution tests lead to rapid dissolution rates for nanosuspensions, causing difficulties in discriminating dissolution profiles between different formulations. Here, non-sink conditions were studied for the dissolution testing of poorly water-soluble drug nanosuspensions. A mathematical model for polydispersed particles was established to clarify dissolution mechanisms. The dissolution of nanosuspensions with either a monomodal or bimodal size distribution was simulated. In the experimental part, three different particle sizes of indomethacin nanosuspensions were prepared by the wet milling technique. The effects of the dissolution medium pH and agitation speed on dissolution rate were investigated. The dissolution profiles in sink and non-sink conditions were obtained by changing the ratio of sample amount to the saturation solubility. The results of the simulations and experiments indicated that when the sample amount was increased to the saturation solubility of drug, the slowest dissolution rate and the best discriminating dissolution profiles were obtained. Using sink conditions or too high amount of the sample will increase the dissolution rate and weaken the discrimination between dissolution profiles. Furthermore, the low solubility by choosing a proper pH of the dissolution medium was helpful in getting discriminating dissolution profiles, whereas the agitation speed appeared to have little influence on the dissolution profiles. This discriminatory method is simple to perform and can be potentially used in any nanoproduct development and quality control studies.

Background: In this paper a specialist in general practice is referred to as a general practitioner (GP). In Finland only half of all GPs work as a health centre physician. The present aim was to establish what the working places of specializing and specialized physicians in general practice are, and where they assume they will work in the future., Methods: The study population comprised 5,357 physicians licensed in Finland during the years 1977-1996. Altogether 2,956 questionnaires were returned, a response rate of 55.2%. Those either specializing (GP trainees, n=133) or already having specialized (GPs, n=426) in general practice were included in the study. Respondents were asked what kind of physician's work they would most preferably do. They were further asked what work they assumed they would be doing in the year 2020., Results: Altogether 72% were working in public primary health centres and 14% in the private sector. Of GPs 53% and of GP trainees 70% would most preferably work in health centres. Of GPs 14% would most preferably work as private practitioners and 9% as occupational health physicians. Sixteen per cent assumed they would be working as private practitioners and 35% assumed they would be retired in the year 2020. Of GP trainees 57% assumed they would be working as health centre physicians in 2020., Conclusions: According to the present findings many experienced GPs will leave their work as a health centre physician. Moreover, several GP trainees do not consider health centre physician's work as a long-term career option. These trends may in the future reflect a recruiting problem in many primary health centres.

Background: Retrospective assessment of surgery outcome is considered problematic. The aims of this study were to evaluate the reproducibility and accuracy of a retrospective outcome assessment of lumbar spinal stenosis surgery with reference to prospective outcome scale measurements., Method: Outcome of surgery from 100 lumbar spinal stenosis (LSS) patients was evaluated retrospectively from patient files of a 3-month outpatient visit performed according to a standard clinical protocol by two independent researchers. In the retrospective analysis, outcome was graded as 2 = good if the clinical condition had clearly improved, 1 = moderate if it had just slightly improved, 0 = poor if it had not improved or was even worse than before the surgical treatment (Retrospective 3- point scale). A prospectively assessed Oswestry Disability Index questionnaire (ODI), Visual analogue pain scale (VAS) and a patient satisfaction questionnaire were used as references of standards. Reproducibility of the measurements was evaluated., Results: The retrospective 3-point scale correlated with ODI (r = 0.528; P < 0.001) and VAS (r = 0.368; P < 0.001). The agreement was better in the good and poor outcome than in the moderate outcome. Retrospective 3-point scale demonstrated substantial intra-rater and inter-rater repeatability (κ = 0.682, P < 0.001 and κ = 0.630, P < 0.001, respectively)., Conclusions: Retrospective assessment of spinal surgery outcome is highly reproducible. Accuracy is highest in the patients with poor and good surgical result.

Previous studies comparing SAR difference in the head of children and adults used highly simplified generic models or half-wave dipole antennas. The objective of this study was to investigate the SAR difference in the head of children and adults using realistic EMF sources based on CAD models of commercial mobile phones. Four MRI-based head phantoms were used in the study. CAD models of Nokia 8310 and 6630 mobile phones were used as exposure sources. Commercially available FDTD software was used for the SAR calculations. SAR values were simulated at frequencies 900 MHz and 1747 MHz for Nokia 8310, and 900 MHz, 1747 MHz and 1950 MHz for Nokia 6630. The main finding of this study was that the SAR distribution/variation in the head models highly depends on the structure of the antenna and phone model, which suggests that the type of the exposure source is the main parameter in EMF exposure studies to be focused on. Although the previous findings regarding significant role of the anatomy of the head, phone position, frequency, local tissue inhomogeneity and tissue composition specifically in the exposed area on SAR difference were confirmed, the SAR values and SAR distributions caused by generic source models cannot be extrapolated to the real device exposures. The general conclusion is that from a volume averaged SAR point of view, no systematic differences between child and adult heads were found., (Copyright © 2011. Published by Elsevier Ltd.)

Because of its biocompatibility and ability to accommodate a variety of payloads from poorly soluble drugs to biomolecules, porous silicon (PSi) is a lucrative material for the development of carriers for particle-mediated drug delivery. We report a successful direct one-step (18)F-radiolabeling of three types of PSi microparticles, thermally hydrocarbonized THCPSi, thermally oxidized TOPSi, and thermally carbonized TCPSi for the investigation of their biodistribution in vivo with positron emission tomography as part of their evaluation as carriers for particle-mediated drug delivery. FTIR and XPS characterization of the PSi materials after carrier-added (18)F/(19)F-radiolabeling reveals that depending on the material the (18)F-labeling is likely to be accomplished either by substitution for surface silyl hydrogen or silyl fluoride or by nucleophilic attack of (18)F(-) to Si-O-Si bridges. With the selected (18)F-radiolabeling method, good to excellent in vitro radiolabel stability in simulated gastric and intestinal fluids and in plasma is achieved for all the particle types studied. Finally, a preliminary evaluation of (18)F-THCPSi microparticle biodistribution in the rat gastrointestinal tract after oral administration is reported, illustrating the utility of using (18)F-radiolabeled PSi as imaging probes for PSi-based drug delivery carrier distribution in vivo.

Stability of high indomethacin (IMC) content formulations based on ordered mesoporous silica MCM-41 and SBA-15 materials was studied before and after a 3 month storage in stressed conditions (30°C/56% RH). Overall, the physical stability of the samples was found satisfactory after the storage. However, some issues with the chemical stability were noted, especially with the MCM-41 based samples. The stability issues were evident from the decreased HPLC loading degrees of the drug after stressing as well as from the observed extra peaks in the HPLC chromatograms of the drug in the stressed samples. Drug release from the mesoporous formulations before stressing was rapid at pH 1.2 in comparison to bulk crystalline IMC. The release profiles also remained similar after stressing. Even faster and close to complete IMC release was achieved when the pH was raised from 1.2 to 6.8. To our knowledge, this is the first report of chemical stability issues of drugs in mesoporous silica drug formulations. The present results encourage further study of the factors affecting the chemical stability of drugs in mesoporous silica MCM-41 and SBA-15 formulations in order to realize their potential in oral drug delivery., (Copyright © 2011 Elsevier B.V. All rights reserved.)

A poorly soluble model drug, indomethacin (IMC), was loaded into two types of silica particles using three different loading methods. The loading efficiency and the extent/rate of drug release were evaluated. Widely used equipment in pharmaceutical laboratories, rotavapor and fluid bed, were used in the loading. The porous materials used were ordered mesoporous silica MCM-41 and nonordered silica gel Syloid 244 FP EU. The materials differ both in their pore properties and particle sizes. Tablets were successfully compressed from the IMC-loaded particles. Mechanical stability of the porous structures was studied with XRPD and nitrogen sorption after tableting and drug release was evaluated at pH 5.5 before and after tableting. The release of the poorly soluble IMC was faster from the Syloid than from the MCM-41, presumably due to the larger pore size and smaller particle size. Loading of IMC into the MCM-41 microparticles improved the drug dissolution, and blending the microparticles with pharmaceutical excipients improved the IMC release even further. The fast release was also maintained after tableting. Loading of IMC into the Syloid particles alone was sufficient to produce similar IMC release profiles, as in the case of MCM-41 with the excipients., (Copyright © 2011 Wiley-Liss, Inc.)

Mesoporous materials have an ability to enhance dissolution properties of poorly soluble drugs. In this study, different mesoporous silicon (thermally oxidized and thermally carbonized) and non-ordered mesoporous silica (Syloid AL-1 and 244) microparticles were compared as drug carriers for a hydrophobic drug, itraconazole (ITZ). Different surface chemistries pore volumes, surface areas, and particle sizes were selected to evaluate the structural effect of the particles on the drug loading degree and on the dissolution behavior of the drug at pH 1.2. The results showed that the loaded ITZ was apparently in amorphous form, and that the loading process did not change the chemical structure/morphology of the particles' surface. Incorporation of ITZ in both microparticles enhanced the solubility and dissolution rate of the drug, compared to the pure crystalline drug. Importantly, the physicochemical properties of the particles and the loading procedure were shown to have an effect on the drug loading efficiency and drug release kinetics. After storage under stressed conditions (3 months at 40 °C and 70% RH), the loaded silica gel particles showed practically similar dissolution profiles as before the storage. This was not the case with the loaded mesoporous silicon particles due to the almost complete chemical degradation of ITZ after storage., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Several mono- and bimetallic Pd, Pt, Rh and Ru supported on alumina and active carbon catalysts were characterized by CO chemisorption, nitrogen adsorption, XPS and XRD and acidity titrations were performed for active carbon supported catalysts. These catalysts were tested in oxidation of two sugars, namely lactose and rhamnose, at 60 °C and at 70 °C under slightly alkaline conditions (pH 8) with molecular oxygen. The results revealed that there is an optimum metal particle size in a range of 3-10 nm giving the highest initial TOFs for both oxidations. Furthermore, the catalytic activities and conversions were related to other catalyst properties, such as the type and amount of promoters and the presence of different phases. In situ catalyst potential measurements revealed that there is an inverse correlation between the increase of catalyst potential as a function of sugar conversion and the catalyst activity after prolonged reaction times. This method is a valuable tool for in situ characterization of catalysts correlating well with their activities., (This journal is © the Owner Societies 2011)

This study was conducted to develop a high throughput screening (HTS) method for the assessment of equilibrium solubility of drugs. Solid-state compounds were precipitated from methanol in 96-well plates, in order to eliminate the effect of co-solvent. Solubility of twenty model drugs was analyzed in water and aqueous solutions (pH 1.2 and 6.8) in 96-well plates and in shake-flasks (UV detection). The results obtained with the 96-well plate method correlated well (R(2)=0.93) between the shake-flask and 96-well plates over the wide concentration scale of 0.002-169.2mg/ml. Thereafter, the solubility tests in 96-well plates were performed using fasted state human intestinal fluid (HIF) from duodenum of healthy volunteers. The values of solubility were similar in phosphate buffer solution (pH 6.8) and HIF over the solubility range of 10(2)-10(5)μg/ml. The new 96-well plate method is useful for the screening of equilibrium drug solubility during the drug discovery process and it also allows the use of human intestinal fluid in solubility screening., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Choosing a medical specialty is an important element predefining a physician's career and life. Although there has been some research in this area of interest, there has not been much research where the profession has been researched as a whole, or where trend data over different generations has been presented., Aim: The aim of our study was to ascertain the motives affecting physicians' choice of a medical specialty., Methods: The study cohort comprised random sample of 7758 doctors who were registered in Finland during the years 1977-2006. Altogether 4167 questionnaires were returned, giving a response rate of 54%. An electronic questionnaire was used in data collection, supported by a traditional postal questionnaire., Results: Of the respondents, 76% thought the diversity of the field had affected their choices of specialty considerably or very much. For physicians under 35 years old, especially the good example set by colleagues (48%), and opportunities for career development (39%) were more important motives compared to those of older physicians., Conclusions: According to this study, diversity of the work is the main motivating factor affecting physicians' choices of specialty. Especially, younger physicians follow the example set by more experienced colleagues.

Conclusion: Difficulties in diagnosis, conservative initial steps in the management algorithm and intraoperative risks for facial nerve (FN) injury are divisive features for this tumour entity., Objective: The aim of the present study was to investigate the management and outcome of FN schwannomas (FNSs) at a tertiary referral centre and academic institution in a 30-year material., Methods: Data on age, sex, symptoms, tumour location, histopathological characteristics, imaging, management and outcome were retrospectively recorded., Results: Ten cases (six males, 60%), with a median age of 34.5 years (range 19-75 years) were identified. Five of the patients had intact FN function at the time of diagnosis. Five of the tumours were intraparotid and five were located in the temporal bone. Preoperative fine needle aspirations were non-diagnostic in all of the four patients presenting with a parotid mass. Nine patients were managed surgically. One patient is currently under conservative follow-up for a parotid schwannoma (diagnosed with magnetic resonance imaging) with intact FN function. No malignant schwannomas were encountered. The clinical outcome and histology will be discussed.

We report here the in vitro cytotoxicity of mesoporous silicon (PSi) microparticles on the Caco-2 cells as a function of particle size fractions (1.2-75 microm), particle concentration (0.2-4 mg ml(-1)) and incubation times (3, 11 and 24 h). The particle size (smaller PSi particles showed higher cytotoxicity) and the surface chemistry treatment of the PSi microparticles were considered to be the key factors regarding the toxicity aspects. These effects were significant after the 11 and 24 h exposure times, and were explained by cell-particle interactions involving mitochondrial disruption resulting from ATP depletion and reactive oxygen species production induced by the PSi surface. These events further induced an increase in cell apoptosis and consequent cell damage and cell death in a dose-dependent manner and as a function of the PSi particle size. These effects were, however, less pronounced with thermally oxidized PSi particles. Under the experimental conditions tested and at particle sizes >25 microm, the non-toxic threshold concentration for thermally hydrocarbonized and carbonized PSi particles was <2 mg ml(-1), and for thermally oxidized PSi microparticles was <4 mg ml(-1)., (Copyright 2009 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Cytotoxicity of ordered mesoporous silica MCM-41 and SBA-15 microparticles (fractions between 1 and 160 microm) was determined in vitro on undifferentiated human colon carcinoma (Caco-2) cell line, considering the feasibility of using these silica-based materials in oral drug formulations. The cellular endpoints employed for assessing the effects of the MCM-41 and SBA-15 microparticles on Caco-2 were: (1) cell membrane integrity by monitoring live-cell protease activity (AFC) and by employing the flow cytometry method; (2) metabolic activity by monitoring total ATP content via luminescence assay; (3) activity of apoptotic effectors by caspase-3/7 activity assay. The generation of reactive oxygen species (ROS) was also followed, specifically the hydrogen peroxide (H(2)O(2)) and the superoxide radical (O(2)(-)). MCM-41 and SBA-15 microparticles caused cytotoxic effects on the Caco-2 cells, at most tested concentrations (0.2-14 mg/ml) and incubation times (3 and 24h). The effects on the cells included weakened cell membrane integrity, diminished cell metabolism and increased apoptotic signalling. The root cause for the cytotoxicity was heightened production of reactive oxygen species (ROS), especially the formation of the superoxide radical O(2)(-) already after 3h incubation with threshold dose 1mg/ml, apparently overwhelming the antioxidant defences and causing mitochondrial dysfunction, hence increasing the apoptotic signalling., ((c) 2009 Elsevier B.V. All rights reserved.)

Pyrimidine biosynthesis is an attractive drug target in a variety of organisms, including humans and the malaria parasite Plasmodium falciparum. Dihydroorotate dehydrogenase, an enzyme catalyzing the only redox reaction of the pyrimidine biosynthesis pathway, is a well-characterized target for chemotherapeutical intervention. In this study, we have applied SPROUT-LeadOpt, a software package for structure-based drug discovery and lead optimization, to improve the binding of the active metabolite of the anti-inflammatory drug leflunomide to the target cavities of the P. falciparum and human dihydroorotate dehydrogenases. Following synthesis of a library of compounds based upon the SPROUT-optimized molecular scaffolds, a series of inhibitors generally showing good inhibitory activity was obtained, in keeping with the SPROUT-LeadOpt predictions. Furthermore, cocrystal structures of five of these SPROUT-designed inhibitors bound in the ubiquinone binding cavity of the human dihydroorotate dehydrogenase are also analyzed.

In this work, it is shown that the common toxicity indicator, MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide), will fail to predict the toxicity of porous silicon (PSi) microparticles. This is due to the spontaneous redox reactions where the MTT is reduced and the PSi particle surfaces are oxidized simultaneously. MTT was shown to even react with thermally oxidized and carbonized forms of PSi particles, although the treatment did give an enhanced protection against the unwanted reactions as compared to as-anodized PSi particles. The observed levels of cellular viability with the MTT assay were much higher than expected in the presence of Caco-2 cells, even considering the spontaneous reduction of MTT at PSi surfaces. The results indicate that the redox reaction is further enhanced inside living cells. Thus, we recommend that MTT should not be used to test the cytotoxicity of drug formulations containing PSi microparticles. The study also shows that since PSi particles are capable of reducing the MTT, they will also be able to reduce other species as well. This should be taken into account when considering future applications for the porous silicon particles. The completely oxidized SiO2 particles (MCM-41 and SBA-15) were shown to work as expected with the MTT assay and showed no inherent oxidation/reduction.

The feasibility of four mesoporous materials composed of biocompatible Si (TCPSi) or SiO(2) (MCM-41, SBA-15, and TUD-1) were evaluated for oral drug delivery applications. The main focus was to study the effect of the materials different pore systems (unidirectional/2D/3D) and their pore diameters, pore size distributions, pore volumes on the maximal drug load capacity, and release profiles of a loaded active pharmaceutical ingredient. Ibuprofen was used as the model drug. The total pore volume of the mesoporous solid was the main factor limiting the maximum drug load capacity, with SBA-15 reaching a very high drug load of 1:1 in weight due to its high pore volume. Dissolution experiments were performed in HBSS buffers of pH 5.5, 6.8, and 7.4 to mimic the conditions in the small intestine. At pH 5.5 the dissolution rate of ibuprofen released from the mesoporous carriers was significantly faster compared with the standard bulk ibuprofen (86-63% versus 25% released at 45 min), with the fastest release observed from the 3D pore network of TUD-1 carrier. The utilization of mesoporous carriers diminished the pH dependency of ibuprofen dissolution (pK(a) = 4.42), providing an interesting prospect for the formulation of poorly soluble drug compounds.

Purpose: The present study describes the crystal structure changes of gamma-cyclodextrin (gamma-CD) during the solution enhanced dispersion by supercritical fluids (SEDS) process and its effect on dissolution behaviour of complexed budesonide., Materials and Methods: gamma-CD solution (10 mg/ml in 50% ethanol) was pumped together with supercritical carbon dioxide through a coaxial nozzle with or without a model drug, budesonide (3.3 mg/ml). The processing conditions were 100 b and 40, 60 or 80 degrees C. gamma-CD powders were characterised before and after vacuum-drying (2-3 days at RT) with XRPD, SEM and NMR. Budesonide/gamma-CD complexation was confirmed with DSC and XRPD. The dissolution behaviour of complexed budesonide was determined in aqueous solution (1% gamma-CD, 37 degrees C, 100 rpm)., Results: During the SEDS process (100 b, 40 and 60 degrees C), gamma-CD and budesonide/gamma-CD complexes crystallized in a tetragonal channel-type form. The vacuum-drying transformed crystalline gamma-CD into amorphous form while the complexes underwent a tetragonal-to-hexagonal phase transition. The increase in the processing temperature decreased the crystallinity of gamma-CD. At 80 degrees C, amorphous gamma-CD was obtained while the complexes crystallized in a hexagonal channel-type form. The dissolution behaviour of budesonide/gamma-CD complexes was dependent on their crystal structure: the tetragonal form dissolved faster than the hexagonal form., Conclusions: The crystal structure of gamma-CD and subsequently, the dissolution rate of complexed budesonide, can be modified with the processing conditions.

The combined release and permeation behavior of furosemide loaded into thermally carbonized mesoporous silicon (TCPSi) microparticles was studied in order to evaluate the potential of TCPSi-loading to improve permeation of furosemide, a BCS class IV compound. Permeation was studied across Caco-2 monolayers at pH 5.5, 6.8 and 7.4 from drug solutions and TCPSi particles. TCPSi-loaded furosemide (39% w/w) exhibited improved dissolution from the microparticles with greatly diminished pH dependence. At pH 5.5, where furosemide solubility restricted the amount that could be dissolved in the control solution to less than 30% of the dose contained in the TCPSi particles, the flux of TCPSi-loaded furosemide across Caco-2 monolayers was over fivefold compared to pre-dissolved furosemide. The improved permeation could be confirmed also from dose-corrected (% dose-permeated) results. At pH 6.8 and pH 7.4, where corresponding doses could be used in control solutions, more than fourfold permeability values were obtained with TCPSi-loaded furosemide. Effects on transepithelial electrical resistance (TEER) and mannitol permeability were monitored and suggest that monolayer integrity was not compromised by the drug-loaded TCPSi microparticles. The improved permeation observed from furosemide-loaded TCPSi particles suggests that the high local concentrations provided by the enhanced dissolution properties of TCPSi-loaded furosemide could prove beneficial for absorption.

For the first time the feasibility of siliceous mesoporous material TUD-1 (Technische Universiteit Delft) for drug delivery was studied. Model drug, ibuprofen, was adsorbed into TUD-1 mesopores via a soaking procedure. Characterizations with nitrogen adsorption, XRD, TG, HPLC and DSC demonstrated the successful inclusion of ibuprofen into TUD-1 host. The amount of ibuprofen adsorbed into the nanoreservoir of TUD-1 material was higher than reported for other mesoporous silica drug carriers (drug/carrier 49.5 wt.%). Drug release studies in vitro (HBSS buffer pH 5.5) demonstrated a fast and unrestricted liberation of ibuprofen, with 96% released at 210 min of the dissolution assay. The drug dissolution profile of TUD-1 material with the random, foam-like three-dimensional mesopore network and high accessibility to the dissolution medium was found to be much faster (kinetic constant k = 10.7) and more diffusion based (release constant n = 0.64) compared to a mesoporous MCM-41 material with smaller, unidirectional mesopore channels (k = 4.7, n = 0.71). Also, the mesoporous carriers were found to significantly increase the dissolution rate of ibuprofen, when compared to the pure crystalline form of the drug (k = 0.6, n = 0.96). TUD-1 was constituted as a potential drug delivery device with fast release property, with prospective applications in the formulation of poorly soluble drug compounds.

Influence of preparation methods and ultrasound irradiation on physico-chemical and catalytic properties was investigated by synthesizing Pt-ZSM-5 and Pt-Beta catalysts by in-situ and impregnation methods and applying ultrasound irradiation to synthesis gel mixture of ZSM-5 and Beta zeolites. It was concluded from the X-ray powder diffraction patterns of Pt-ZSM-5 and Pt-Beta zeolite catalysts that introduction of Pt by in-situ method and ultrasound irradiation did not influence the structures of ZSM-5 and Beta zeolites. Morphology of ZSM-5 and Beta zeolites were investigated by scanning electron microscopy. SEM micrographs showed that the Pt-ZSM-5-IS-US catalyst synthesized by in-situ method with ultrasound irradiation resulted in smaller crystals of ZSM-5 than Pt-ZSM-5-IS catalyst prepared without ultrasound irradiation. Furthermore SEM micrographs of Pt-Beta-11-IS-US zeolite synthesized using ultrasound irradiation showed much smaller crystals than Pt-Beta-11-IM indicating that ultrasound irradiation had a significant effect on the morphology of Beta zeolite. Conversion of n-pentane and selectivity to iso-pentane over the Pt-ZSM-5-IS-US zeolite catalysts prepared by ultrasound irradiation during in-situ introduction of platinum was higher than the catalysts prepared without the ultrasound irradiation. Furthermore ultrasound irradiated and in-situ synthesized Pt-Beta-11-IS-US catalyst also showed higher selectivity to iso-pentane than Pt-H-Beta-11-IM prepared by impregnation method.

Pyrimidine biosynthesis presents an attractive drug target in malaria parasites due to the absence of a pyrimidine salvage pathway. A set of compounds designed to inhibit the Plasmodium falciparum pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (PfDHODH) was synthesized. PfDHODH-specific inhibitors with low nanomolar binding affinities were identified that bind in the N-terminal hydrophobic channel of dihydroorotate dehydrogenase, the presumed site of ubiquinone binding during oxidation of dihydroorotate to orotate. These compounds also prevented growth of cultured parasites at low micromolar concentrations. Models that suggest the mode of inhibitor binding is based on shape complementarity, matching hydrophobic regions of inhibitor and enzyme, and interaction of inhibitors with amino acid residues F188, H185, and R265 are supported by mutagenesis data. These results further highlight PfDHODH as a promising new target for chemotherapeutic intervention in prevention of malaria and provide better understanding of the factors that determine specificity over human dihydroorotate dehydrogenase.

The aim was to investigate if solid drug/cyclodextrin complexes could be produced in a single-step process with a solution enhanced dispersion by supercritical fluids (SEDS) method. Budesonide and gamma-cyclodextrin (CD) solutions (50% or 99.5% ethanol) were pumped from the same (conventional method) or separate (modified method) containers together with supercritical carbon dioxide through a coaxial nozzle into a particle formation chamber. The pressure was maintained at 100, 150 or 200 bar with a temperature of 40, 60 or 80 degrees C. SEDS-processed powders were characterised with HPLC, DSC and XRPD for budesonide content, complexation and crystallinity. The budesonide dissolution rate was determined in 1% gamma-CD aqueous solution. Solid, white budesonide/gamma-CD complex particles were formed using the conventional and modified SEDS processes. The complexation efficiency was dependent on the processing conditions. For example, with the conventional method (100 bar, 60 degrees C) the yield of the powder was 65+/-12% with 0.14+/-0.02 mg budesonide/mg powder, corresponding to 1:2 drug:CD molar ratio. The dissolution rate of this complexed budesonide (93+/-2% after 15 min) was markedly higher compared to unprocessed micronised budesonide (41+/-10%) and SEDS-processed budesonide without CD (61+/-3%). As a conclusion, SEDS is a novel method to produce solid drug/CD complexes in a single-step process., (Copyright (c) 2006 Wiley-Liss, Inc. and the American Pharmacists Association)

Objective: Computerised surveillance systems have become available for screening potential adverse drug interactions during drug prescribing and dispensing. The purpose of this study was to analyse the frequency and profile of alerts given by one such system in two community pharmacies in Finland., Methods: In a prospective study, all interaction alerts given by the surveillance system were collated during September-November 2004 in two community pharmacies in Southern Finland. The alerts were categorised into four classes (A-D) according to their clinical significance., Results: During the 3-month study period, a total of 39,539 prescriptions were dispensed. The system flagged 3,861 prescriptions as having potential interactions (9.8% of all prescriptions). Since one prescription could be the source of several interaction alerts, a total of 5,647 alerts were given. The clinically most significant interactions (class D) represented 0.4% of prescriptions (3.0% of all interactions). Class C alerts were most prevalent (9.4% of all prescriptions, 65.9% of all interactions). The most commonly encountered interaction in class D was between warfarin and non-steroidal anti-inflammatory drugs., Conclusions: Although the incidence of potentially most hazardous interactions in prescriptions is rather low in this study (0.4%), the overall incidence is relatively high (9.8%). Implementation of the interaction surveillance system in the participating pharmacies makes it possible to study in the future in quantitative terms whether the quality of drug dispensing is improved.

The de novo molecular design program SPROUT has been applied to the X-ray crystal structures of Plasmodium and human dihydroorotate dehydrogenase, respectively. The resulting design templates were used to prepare a series of molecules which, in keeping with predictions, showed useful levels of species-selective enzyme inhibition.

Mesoporous silicon (PSi) microparticles were produced using thermal carbonization (TCPSi) or thermal oxidation (TOPSi) to obtain surfaces suitable for oral drug administration applications. The loading of five model drugs (antipyrine, ibuprofen, griseofulvin, ranitidine and furosemide) into the microparticles and their subsequent release behaviour were studied. Loading of drugs into TCPSi and TOPSi microparticles showed, that in addition to effects regarding the stability of the particles in the presence of aqueous or organic solvents, surface properties will affect compound affinity towards the particle. In addition to the surface properties, the chemical nature of the drug and the loading solution seems to be critical to the loading process. This was reflected in the obtained loading efficiencies, which varied between 9% and 45% with TCPSi particles. The release rate of a loaded drug from TCPSi microparticles was found to depend on the characteristic dissolution behaviour of the drug substance. When the dissolution rate of the free/unloaded drug was high, the microparticles caused a delayed release. However, with poorly dissolving drugs, the loading into the mesoporous microparticles clearly improved dissolution. In addition, pH dependency of the dissolution was reduced when the drug substance was loaded into the microparticles.

Objective: To evaluate serology with novel Borrelia-specific protein or peptide antigens in the laboratory diagnosis of neuroborreliosis (NB) in children., Methods: The performance of enzyme-linked immunosorbent assays with several recombinant borrelial protein antigens and invariable region 6 synthetic peptide antigen and of a commercial enzyme-linked immunosorbent assay with the flagella antigen were evaluated in the serodiagnosis and follow-up of children with clinical suspicion of NB. Serum samples were obtained from 20 children with neurologic symptoms indicative of NB. The patients were retrospectively divided into 2 groups based on the laboratory tests at presentation indicating definite (n = 7) or probable (n = 13) NB., Results: In addition to cerebrospinal fluid (CSF) lymphocytic pleocytosis and CSF antiflagella antibodies, all 7 patients with definite NB had serum IgG antibodies to at least 2 of the 3 novel antigens at presentation. The 13 patients with probable NB had variable laboratory findings: CSF pleocytosis (n = 7), CSF antiflagella IgM antibodies (n = 4), serum antiflagella IgM and/or IgG antibodies (n = 10). Of these 13 patients, 7 had serum IgG antibodies to 2 of the 3 novel antigens at presentation. During long term follow-up, serum anti-invariable region 6 antibodies disappeared., Conclusions: The present study suggests that assessment of serum antibodies to a panel of Borrelia-specific antigens could improve the laboratory diagnosis of NB at presentation.

The crystallographic texture, i.e. the preferred orientation of crystallites of delta-mannitol samples, has been experimentally determined by pole figure analysis. The pole figures were measured with an X-ray diffraction texture goniometer. It was found that already the uncompressed delta-mannitol powder sample was slightly texturized so that the (0 2 0) plane was parallel to the upper surface of the sample. The degree of preferred orientation was found to significantly increase when the powder was compressed to a tablet with the minimum (74MPa) compression pressure. Nevertheless, the direction of the texture remained parallel to the tablet surface. Maximum compression (740MPa) did not increase the degree of preferred orientation further. The compression time (0 or 60s) was not found to noticeably affect the strength or direction of the texture. The extent of the texture inside the tablet was determined with a tablet surface grinding experiment. The degree of preferred orientation was found to decrease under the surface while the orientation remained the same. The results were confirmed with orientation distribution function (ODF) calculations.

Three recombinant antigens, decorin binding protein A (DbpA), BBK32, and outer surface protein C (OspC), and IR(6) peptide of borrelial VlsE protein, were evaluated for the diagnosis of neuroborreliosis (NB), using cerebrospinal fluid (CSF) and serum samples from 89 patients. Their performances in enzyme-linked immunosorbent assay (ELISA) were compared with that of commercial flagella antigen. IgG ELISAs were performed with three variants of each recombinant antigen originating from Borrelia burgdorferi sensu stricto, B. afzelii and B. garinii, and with the IR(6) peptide. IgM antibodies were analysed against OspC and flagella. Of the patients whose CSF contained elevated anti-flagella IgG antibodies, 93% were positive for at least three of the new antigens. Of those with negative or borderline CSF anti-flagella antibodies, 51% were positive for three new antigens. Antibodies to BBK32 were detectable mainly in early disease. Antibodies to DbpA and IR(6) were observed in early and late NB. The use of the new antigens at presentation of the disease improved the laboratory diagnosis of NB. In IgG ELISAs, the diagnostic sensitivity of assays with the new antigens was between 75 and 88%, but was only 52% with the flagella antigen. The discriminatory power between patient and control samples appeared better in the CSF than in the serum. We suggest that assessment of CSF antibodies to at least two antigens, using either flagella and one of the new antigens or two of the new antigens, would improve the current diagnostic yield of NB.

A new modification of the channel flow dissolution method is introduced together with the theoretical basis to extract the solubility and mass transfer parameters from the dissolution experiments. Correlation of drug dissolution profiles in the channel flow apparatus was evaluated with respect to USP basket and intrinsic dissolution methods at pH 1.2 or 6.8. Acetylsalicylic acid (ASA) was studied as a pure drug substance and as three simple tablet compositions with microcrystalline cellulose (MCC) and/or lactose as excipients. The channel flow measurements of 100% ASA tablets correlated well with the results of intrinsic dissolution tests. In the channel flow method as well as in the USP basket method the release of ASA was fastest from the tablet compositions containing lactose, while the slowest dissolution rate was observed with the composition containing MCC as the only excipient. As presumed, the dissolution rate of the weak acid was decreased as the pH of the medium was lowered, which was clearly confirmed also by the three dissolution methods. MCC forms matrix tablets and in the USP basket method the dissolution profiles followed square root of time kinetics indicating that diffusion was the rate-controlling step of ASA dissolution. Also the channel flow results indicated that the dissolution of ASA was controlled by mass transfer. The swelling behaviour of the tablets is different in the channel flow method as compared to the basket method: only one tablet surface is exposed to the dissolution medium in the channel flow system. The contact between the tablet surface and the dissolution medium is more similar between the channel flow and intrinsic dissolution methods.

The performances of recombinant borrelial BBK32 proteins as antigens in the serology of erythema migrans (EM) were evaluated in an ELISA. Serum samples were obtained from 75 patients from different geographic areas where three borrelial species, Borrelia burgdorferi sensu stricto, Borrelia afzelii or Borrelia garinii, cause Lyme borreliosis. Antibodies to variant BBK32 proteins were compared with anti-flagella or with anti-IR(6) peptide antibodies. In IgG ELISA at presentation of EM, 65/75 (87 %) patients had antibodies to one or more variants of BBK32, 29/75 (39 %) had antibodies to flagella and 29/75 (39 %) had antibodies to the VlsE IR(6) peptide antigen. The immunoreactivity against variant BBK32 proteins differed in patients from different geographic regions. The present results suggest that the BBK32 proteins used in combination or in parallel may improve the laboratory diagnosis of EM.

The performance of ELISAs with the recombinant antigens decorin-binding protein A (DbpA), DbpB, and BBK32 (from Borrelia afzelii, B. garinii, and B. burgdorferi sensu stricto) and VlsE peptide antigen invariable region 6 (IR(6)) were evaluated in the serodiagnosis and follow-up of children with Lyme arthritis (LA). Serum samples were obtained from 52 children with clinically typical and serologically confirmed LA. In IgG ELISAs, at diagnosis, 50 samples were positive for BBK32, 51 for DbpA, 40 for DbpB, and 51 for IR(6). In the posttreatment follow-up, the rate of decline of the antibodies to the recombinant protein antigens or to IR(6) did not appear useful in the prediction of the treatment response or the clinical course of LA. Yet, IR(6) seems to have the greatest potential to be used universally in the diagnostic serology of Lyme borreliosis (LB). Alternate to that, the use of several specific borrelial antigens, in parallel, might improve the accuracy of serology for LB.

Genes for the outer-surface protein C (OspC) from three north European human isolates of Borrelia burgdorferi sensu stricto, B. afzelii and B. garinii were cloned and sequenced. Polyhistidine-tagged recombinant OspC (rOspC) proteins were produced in Escherichia coli and used, after biotinylation, as antigens on streptavidin-coated plates in enzyme-linked immunosorbent assays (ELISA). In IgM ELISA, 30% (5/17) and 35% (6/17) of patients with erythema migrans (EM) in the acute or convalescent phase, respectively, reacted with one to three rOspCs. Of the patients, 53% (8/15) with neuroborreliosis (NB) and 53% (8/15) with Lyme arthritis (LA) had IgM antibodies to OspC. The immunoreactivity was stronger against rOspC from B. afzelii and B. garinii than against rOspC from B. burgdorferi sensu stricto. In early Lyme borreliosis (LB), rOspC and flagella performed equally well in detecting IgM antibodies. Cross-reactive antibodies to rOspC were observed in serum samples from patients with rheumatoid factor positivity and with syphilis or Epstein-Barr virus (EBV) infection. In IgM ELISA, thiocyanate in the serum dilution buffer reduced EBV-associated non-specific positive reactions. Of the patient sera examined in IgG ELISA, 30% (5/17) with EM in the acute phase, 35% (6/17) with EM in the convalescent phase, 33% (5/15) with NB and 60% (9/15) with LA were positive. Because of the heterogeneity of OspC, a polyvalent antigen with several OspC variants from at least B. afzelii and B. garinii is needed to improve the sensitivity of OspC ELISA in the serodiagnosis of LB in Europe.