Differential macrophage expression of IL-12 and IL-23 upon innate immune activation defines rat autoimmune susceptibility

Rodents typically demonstrate strain-specific susceptibilities to induced autoimmune models such as experimental arthritis and encephalomyelitis. A common feature of the local pathology of these diseases is an extensive infiltration of activated macrophages (MPhi). Different functional activation states can be induced in MPhi during innate immune activation, and it is this differential activation that might be important in susceptibility/resistance to induction or perpetuation of autoimmunity. In this study, we present an extensive, comparative analysis of the activation phenotypes of MPhi derived from autoimmune-susceptible and autoimmune-resistant rat strains to describe a cellular phenotype that defines the disease phenotype. We included investigation of receptor function, intracellular signaling pathways, cytokines, and other soluble mediators released after activation of cells using a panel of stimuli embracing many activation routes. We report that activation of MPhi from the autoimmune-susceptible strain was associated with alternative activation indicated by induction of arginase activity, a lower production of classical proinflammatory mediators, and a high production of interleukin (IL)-23, and MPhi from the autoimmune-resistant strains were associated with a higher production of proinflammatory mediators, a classical activation phenotype, and preferential induction of IL-12. These MPhi phenotypes thus reflect disparate, genetic cellular programs that define autoimmune susceptibility.     

S100 proteins as cancer biomarkers with focus on S100B in malignant melanoma

Although histochemical staining of the S100 protein family has been used for many years in the diagnosis of malignant melanoma, recent studies suggest one of the proteins comprising the S100 family, S100B, has particular utility in many aspects of the clinical management of malignant melanoma. This protein has been shown to be of use in staging malignant melanoma, in establishing prognosis, in evaluating treatment success and in predicting relapse. S100B is an independent prognostic factor and pretreatment circulating S100B concentrations predict duration of survival in melanoma patients. Survival is significantly longer in melanoma patients with normal S100B levels compared to those with elevated levels. Circulating S100B levels very sensitively detect metastatic growth of malignant melanoma, particularly in stage IV disease where S100B is certainly superior to other laboratory parameters. S100B concentrations reflect tumor mass. Serum S100B levels predict efficacy of treatment. Decreasing S100B concentrations reflect response to therapy while increasing S100B concentrations indicate tumor progression. Circulating S100B has a role to play in the decision to switch treatment regimens.     

Susceptibilities of different Actinobacillus actinomycetemcomitans strains to lactoperoxidase-iodide-hydrogen peroxide combination and different antibiotics

Actinobacillus actinomycetemcomitans has an important aetiological role in localized juvenile periodontitis and in progressive periodontitis in adults. A. actinomycetemcomitans is found mainly in periodontal pockets but also in whole saliva, a potential transmission medium. It is sensitive to peroxidase-halide systems, but the differences between periodontitis associated clinical isolates and type strains are unclear. The sensitivities of these 2 strain groups to lactoperoxidase (LP)-iodide (I(-))-hydrogen peroxide (H(2)O(2)) combinations were investigated, and the sensitivities were compared with the susceptibilities to four antibiotics. There was great variation between the sensitivities of different strains, but the 2 strain groups responded similarly. The LP (75 microg)-I(-) (100 nmol)-H(2)O(2) (1000 nmol) combination produced a similar degree of inhibition as 2 microg ampicillin. The LP-I(-) system might be a potential antimicrobial agent against A. actinomycetemcomitans transmission via saliva.     

Adhesion of soluble fibronectin,vitronectin, and collagen type IV to intraocular lens materials

PURPOSE: To evaluate soluble fibronectin, vitronectin, and collagen type IV adhesion to poly(methyl methacrylate) (PMMA), fluorine-surface-modified PMMA, silicone, hydrophobic and hydrophilic acrylate, and hydrogel intraocular lenses (IOLs) and determine whether hydrophobic and hydrophilic acrylate materials have different fibronectin-adhesion properties. SETTING: Department of Medical Biochemistry, University of Oulu, Oulu, Finland. METHODS: One hundred fifty IOLs were incubated for 1 week at 37 degrees C with radioactive-iodine-labeled soluble fibronectin, vitronectin, or collagen type IV. Fifty IOLs were analyzed for each protein, 5 from each of 10 different IOL models (PMMA, Alcon MC60BM; fluorine-surface-modified PMMA, Chiron Fluorilens Centra-55F; silicone, Allergan Medical Optics SI-40NB and Pharmacia and Upjohn CeeOn 911A; hydrophobic soft acrylate, Alcon AcrySof MA60BM and SA30AL and AMO Sensar; hydrophilic soft acrylate, Ioltech Stabibag and Bausch and Lomb BL27; and hydrogel, Bausch and Lomb Hydroview. The amount of adherent protein was measured with a gamma counter at 1 and 7 days and expressed as counts per minute. RESULTS: At 1 week, significantly more fibronectin was bound to the hydrophobic acrylate IOLs than to the 2-hydroxyethyl methacrylate (HEMA) containing hydrophilic acrylate IOLs (P <.05 to.0001). Significantly more vitronectin was bound to the 2 silicone IOLs than to any other IOL (P <.01 to.0001) at 7 days. Collagen type IV adhered best to the hydrophilic acrylate IOLs, which were significantly different (P <.01 to.0001) than the other IOLs at 1 and 7 days. CONCLUSIONS: Each IOL material had a different affinity to each protein. Significant binding to 1 protein does not indicate that the IOL will bind significantly to all proteins; instead, each protein should be studied separately. Fibronectin bound significantly better to hydrophobic acrylate IOLs than to hydrophilic acrylate IOLs, suggesting that the HEMA-containing IOLs should be classified with the hydrogel IOL group.     

Interrelationships between muscle structure,muscle strength,and running economy

PURPOSE: The present study was designed to investigate possible differences in running economy (RE) among elite middle-distance runners by examining muscle structure and maximal isometric force (MVC). METHODS: Ten young male runners ran at six different running speeds. During the running bouts, respiratory gases, and blood lactate were measured. Muscle biopsies were obtained from the vastus lateralis muscle for analyzing fiber type distribution, muscle fiber area, myosin heavy chain (MHC) composition, activities of a number of metabolic enzymes (citrate synthase, lactate dehydrogenase, phosphofruktokinase, and 3-hydroxyacyl-CoA-dehydrogenase), and titin isoforms. RESULTS: Energy expenditure (EE) increased linearly up to the speed of 6.0 m.s. The relative distribution of the MHC isoforms was MHC I: 67.0%, MHC IIA: 31.5%, and MHC IIX: 1.5%. The present results demonstrated that higher the area of Type II fibers, higher the MVC (r = 0.59, P< 0.05). The amount of MHC II correlated inversely with EE when running close to the competition speed (r = -0.61, P< 0.05). Enzyme activities did not correlate significantly with either RE or EE. Titin analysis revealed that a faster-mobility titin band was observed in all subjects, whereas a lower-mobility titin band was observed only in the most economical runner. CONCLUSION: Differences in RE among homogeneous group of middle-distance runners were observed at various running speeds. This may partly be explained by differences in muscle fiber distribution, MHC composition, and titin isoforms.     

Pharmacokinetics of 10 mg of mifepristone

The results of several randomized studies have verified the efficacy of 10 mg mifepristone in emergency contraception. In the present study we characterized the pharmacokinetics of 10 mg mifepristone. Eight healthy female volunteers received a single oral dose of mifepristone on the day 10 or 11 of their menstrual cycle. Blood samples were collected at 0, 1, 2, 4 and 8 h, daily for the next 6 days and on day 10 after mifepristone. Mifepristone concentrations were determined by radioimmunoassay preceded by column chromatography. A peak level of 1.41 ± 0.31 μmol/L (mean ± SD) was measured at 1 h. Individual elimination phase half-lives varied from 15.3 to 26.8 h, the mean (± SD) value being 19.6 ± 4.50 h. Serum mifepristone concentrations exceeded 10 nmol/L in all volunteers for an average of 4.9 days. The pharmacokinetic data on 10 mg mifepristone are in line with previous pharmacokinetic and clinical data, and encourage further development of the 10-mg dose in emergency contraception.     

Perfusion defect size predicts engraftment but not early retention of intra-myocardially injected cardiosphere-derived cells after acute myocardial infarction

Therapeutic cell retention and engraftment are critical for myocardial regeneration. Underlying mechanisms, including the role of tissue perfusion, are not well understood. In Wistar Kyoto rats, syngeneic cardiosphere-derived cells (CDCs) were injected intramyocardially, after experimental myocardial infarction. CDCs were labeled with [¹⁸F]-FDG (n = 7), for quantification of 1-h retention, or with sodium-iodide-symporter gene (NIS; n = 8), for detection of 24-h engraftment by reporter imaging. Perfusion was imaged simultaneously. Infarct size was 37 ± 9 and 38 ± 9% of LV in FDG and NIS groups. Cell signal was located in the infarct border zone in all animals. No significant relationship was observed between infarct size and 1-h CDC retention (r = −0.65; P = 0.11). However, infarct size correlated significantly with 24-h engraftment (r = 0.75; P = 0.03). Residual perfusion at the injection site was not related to cell retention/engraftment. Larger infarcts are associated with improved CDC engraftment. This observation encourages further investigation of microenvironmental conditions after ischemic damage and their role in therapeutic cell survival.     

A Cluster Randomized Clinical Trial Comparing Functional Capacity Evaluation and Functional Interviewing as Components of Occupational Rehabilitation Programs

Purpose Functional capacity evaluations (FCE) are used to identify work abilities and are commonly integrated into rehabilitation programs. We studied whether integrating FCE into rehabilitation leads to better outcomes for injured workers. Methods A cluster randomised controlled trial was conducted at a workers’ compensation rehabilitation facility (registration ISRCTN61284905). Clinicians were randomised into 2 groups: 1 group used FCE while another conducted semi-structured functional interviews. Outcomes included recommendations following assessment, rehabilitation program outcomes including functional work levels and pain intensity, as well as compensation outcomes at 1, 3, and 6 months after assessment. Analysis included Mann–Whitney U, Chi square and t tests. Results Subjects included 225 claimants of whom 105 were tested with FCE. Subjects were predominantly employed (84 %) males (63 %) with sub-acute musculoskeletal conditions (median duration 67 days). Claimants undergoing FCE had ~15 % higher average functional work levels recommended at time of assessment (Mann–Whitney U = 4,391.0, p < 0.001) but differences at other follow-up times were smaller (0–8 %), in favour of functional interviewing, and not statistically significant. Clinically important improvement during rehabilitation in functional work level (0.9/4, SRM = 0.94), pain intensity (2.0/10, SRM = 0.88) and self-reported disability (21.8/100, SRM = 1.45) were only observed in those undergoing the functional interview. Conclusions Performance-based FCE integrated into occupational rehabilitation appears to lead to higher baseline functional work levels compared to a semi-structured functional interview, but not improved RTW rates or functional work levels at follow-up. Functional interviewing has potential for efficiency gains and higher likelihood of clinically important improvement following rehabilitation, however further research is needed.     

Automated GMP production and long-term experience in radiosynthesis of CB1 tracer [18F]FMPEP-d2

Here, we describe the development of an in-house-built device for the fully automated multistep synthesis of the cannabinoid CB₁ receptor imaging tracer (3R,5R)-5-(3-([¹⁸F]fluoromethoxy-d₂)phenyl)-3-(((R)-1-phenylethyl)amino)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one ([¹⁸F]FMPEP-d₂), following good manufacturing practices. The device is interfaced to a HPLC and a sterile filtration unit in a clean room hot cell. The synthesis involves the nucleophilic ¹⁸F-fluorination of an alkylating agent and its GC purification, the subsequent ¹⁸F-fluoroalkylation of a precursor molecule, the semipreparative HPLC purification of the ¹⁸F-fluoroalkylated product, and its formulation for injection. We have optimized the duration and temperature of the ¹⁸F-fluoroalkylation reaction and addressed the radiochemical stability of the formulated product. During the past 5 years (2013–2018), we have performed a total of 149 syntheses for clinical use with a 90% success rate. The activity yield of the formulated product has been 1.0 ± 0.4 GBq starting from 11 ± 2 GBq and the molar activity 600 ± 300 GBq/μmol at the end of synthesis.     

The fiber and/or polyphenols present in lingonberries null the glycemic effect of the sugars present in the berries when consumed together with added glucose in healthy human volunteers

This study was undertaken on the broad hypothesis that lingonberry (Vaccinium vitis-idaea L.) has potential to reduce postprandial glycemic and lipemic response. More specifically, 2 postprandial crossover studies with healthy normal-weight male subjects were conducted to study the influence of commercial lingonberry powder on postprandial glycemia and lipemia. The test meals contained fat-free yoghurt with either glucose (50 g) or triacylglycerols (35 g) with or without (control) the lingonberry powder. The lingonberry powder provided the meals with a known amount of fiber and a known amount and composition of sugars, and it was a rich source of polyphenols. Postprandial glucose, insulin, and triacylglycerol responses were analyzed. There were no significant differences in the postprandial glucose concentration between the meals in the glycemia trial despite the fact that the lingonberry meal contained more glucose and fructose. When the meal did not contain added sugar but, instead, added triacylglycerol, no glycemia or lipemia-lowering effect was detected. On the contrary, there were indications of higher glycemic and insulinemic effect after the lingonberry meal. The results of this study indicate that the fibers and/or polyphenols present in lingonberries null the glycemic effect of the sugars present in the berries when consumed together with added glucose. By contrast, the lingonberry powder did not affect the postprandial lipemic response.