Cardiac vagal tone, a non-invasive measure of parasympathetic tone, is a clinically relevant tool in Type 1 diabetes mellitus.

AIMS: To compare a novel index of parasympathetic tone, cardiac vagal tone, with established autonomic variables and to test the hypotheses that (1) cardiac vagal tone would be associated with established time and frequency domain measures of heart rate and (2) cardiac vagal tone would be lower in people with Type 1 diabetes than in a matched healthy cohort and lower still in people with established neuropathy. METHODS: Cardiac vagal tone is a validated cardiometrically derived index of parasympathetic tone. It is measured using a standard three-lead electrocardiogram which connects, via Bluetooth, to a smartphone application. A 5-min resting recording of cardiac vagal tone was undertaken and observational comparisons were made between 42 people with Type 1 diabetes and peripheral neuropathy and 23 without peripheral neuropathy and 65 healthy people. In those with neuropathy, 24-h heart rate variability values were compared with cardiac vagal tone. Correlations between cardiac vagal tone and clinical variables were also made. RESULTS: Cardiac vagal tone was lower in people with established neuropathy and Type 1 diabetes in comparison with healthy participants [median (interquartile range) linear vagal scale 3.4 (1.6-5.5 vs 7.0 (5.5-9.6); P < 0.0001]. Cardiac vagal tone was positively associated with time (r = 0.8, P < 0.0001) and frequency domain markers of heart rate variability (r = 0.75, P < 0.0001), representing established measures of parasympathetic function. Cardiac vagal tone was negatively associated with age (r=-0.32, P = 0.003), disease duration (r=-0.43, P < 0.0001) and cardiovascular risk score (r=-0.32, P = 0.006). CONCLUSIONS: Cardiac vagal tone represents a convenient, clinically relevant method of assessing parasympathetic nervous system tone, potentially facilitating the earlier identification of people with Type 1 diabetes who should undergo formal autonomic function testing.

Biodegradation of inorganic drug delivery systems in subcutaneous conditions.

Despite extensive efforts to develop delivery systems for oral administration, subcutaneous (s.c.) injection remains the most common way to administer peptide drugs. To limit the number of frequent injections, sustained release systems that are easy to produce, suitable for various drugs, safe and biodegradable are urgently needed. Porous silicon (PSi) has been recognized to be one of the most promising materials for s.c. peptide delivery, but its biodegradation in s.c. tissue has not been studied in vivo, despite extensive in vitro research. In the present study, differently modified PSi microparticles were injected s.c. in mice, after which the morphology of the particles was thoroughly studied with transmission electron microscopy, micro-computed tomography and X-ray diffraction. Furthermore, histopathology of the s.c. tissue was analyzed to evaluate biocompatibility. To the best of our knowledge, this is the first systematic study which reveals the degradation behavior of various PSi materials in vivo. The PSi surface chemistry significantly affected the biodegradation rate of the s.c. injected microparticles. The most hydrophobic PSi microparticles with hydrocarbonized surface showed the lowest biodegradation rate while the hydrophilic microparticles, with oxide surface, degraded the fastest. The results from different empirical methods complemented each other to deduce the biodegradation mechanism of the inorganic delivery system, providing useful information for future development of s.c. carriers.

The flow properties and presence of crystals in drug-polymer mixtures: Rheological investigation combined with light microscopy.

The presence of solid matter in polymer melts affects the rheological properties of a drug-polymer mixture, and thus the processability of these mixtures in melt-based processes. The particle morphological changes related to dissolution and crystal growth in the mixtures of paracetamol and ibuprofen with polyethylene oxide and methacrylate copolymer (Eudragit® E PO) were observed by polarized microscopy simultaneously while measuring their rheological properties within temperature ranges relevant for melt processes, such as hot melt extrusion and fused deposition modeling 3D printing. The dissolution of solid crystalline matter into the molten polymer and its effects on the rheological parameters showed that the plasticization effect of the drug was highly dependent on the temperature range, and at a temperature high enough, plasticization induced by the small-molecule drugs could enhance the flowability even at very high drug loads. Therefore, even supersaturated mixtures can be plasticized efficiently, enabling their melt processing, such as hot melt extrusion or 3D printing. The combination of rheometry and polarized light microscopy proved to be very useful for studying the link between morphological changes in the drug-polymer and the flow behavior of the drug-polymer mixtures at different temperature ranges and deformation modes.

The effect of poly (lactic-co-glycolic) acid composition on the mechanical properties of electrospun fibrous mats.

The aim of this study was to investigate the influence of polymer molecular structure on the electrospinnability and mechanical properties of electrospun fibrous mats (EFMs). Polymers with similar molecular weight but different composition ratios (lactic acid (LA) and glycolic acid (GA)) were dissolved in binary mixtures of N,N-dimethylformamide (DMF) and tetrahydrofuran (THF). The intrinsic viscosity and rheological properties of polymer solutions were investigated prior to electrospinning. The morphology and mechanical properties of the resulting EFMs were characterized by scanning electron microscope (SEM) and dynamic mechanical analysis (DMA). Sufficiently high inter-molecular interactions were found to be a prerequisite to ensure the formation of fibers in the electrospinning process, regardless the polymer composition. The higher the amount of GA in the polymer composition, the more ordered and entangled molecules were formed after electrospinning from the solution in THF-DMF, which resulted in higher Young's modulus and tensile strength of the EFMs. In conclusion, this study shows that the mechanical properties of EFMs, which depend on the polymer molecule-solvent affinity, can be predicted by the inter-molecular interactions in the starting polymer solutions and over the drying process of electrospinning.

Visualization and prediction of porosity in roller compacted ribbons with near-infrared chemical imaging (NIR-CI).

The porosity of roller compacted ribbon is recognized as an important critical quality attribute which has a huge impact on the final product quality. The purpose of this study was to investigate the use of near-infrared chemical imaging (NIR-CI) for porosity estimation of ribbons produced at different roll pressures. Two off-line methods were utilized as reference methods. The relatively fast method (oil absorption) was comparable with the more time-consuming mercury intrusion method (R(2)=0.98). Therefore, the oil method was selected as the reference off line method. It was confirmed by both reference methods that ribbons compressed at a higher pressure resulted in a lower mean porosity. Using NIR-CI in combination with multivariate data analysis it was possible to visualize and predict the porosity distribution of the ribbons. This approach is considered important for process monitoring and control of continuously operating roller compaction line.

Denervated segments of injured skeletal muscle fibers are reinnervated by newly formed neuromuscular junctions.

A muscle fiber normally receives its innervation at a single neuromuscular junction (NMJ). Transection of myofiber usually leaves one (abjunctional) stump denervated, while the other (adjunctional) remains innervated. To determine the mechanism of reinnervation of the abjunctional stumps, we transected the rat extensor digitorum muscle (EDL) below the site of the distalmost NMJ. Myofiber regeneration was followed for up to 56 days. Reinnervation began with the appearance of irregular acetylcholinesterase and alpha-bungarotoxin-positive deposits on abjunctional stumps after 10 to 15 days. These deposits later developed into more regular NMJ. The newly formed NMJ were innervated by sprouting axons which penetrated through the connective tissue scar separating the stumps. While denervated, the myofibers of the abjunctional segments underwent marked atrophy, which was reversed when reinnervation had ensued. In conclusion, we demonstrate for the first time that mature myofiber segments devoid of previous NMJ can induce both sprouting from intact axon terminals and formation of new "ectopic" NMJ on their own surface. This type of reinnervation is likely to occur only when myofibers are asymmetrically transected by a trauma. The signaling molecules possibly involved in this phenomenon are discussed.

The expression of intermediate filament protein nestin as related to vimentin and desmin in regenerating skeletal muscle.

Intermediate filament (IF) proteins show specific spatial and temporal expression during development of skeletal muscle. Nestin, the least known muscle IF, has an important role in neuronal regeneration. Therefore, we analyzed the expression pattern of nestin as related to that of vimentin and desmin during skeletal muscle regeneration. Nestin and vimentin appear at 6 h post-injury in myoblasts, with maximum expression around day 3-5 post-injury. Thereafter, vimentin expression ceases completely, whereas that of nestin is downregulated to remain only in the sarcoplasm next to neuromuscular and myotendinous junctions. Desmin appears at 6-12 h post-injury and becomes the predominant IF in myofibers simultaneously with the appearance of cross-striations. The expression pattern and colocalization of nestin and vimentin, known to form heteropolymers, suggests that they are essential during the early dynamic phase of the myofiber regeneration when migration, fusion, and structural modeling of myogenic cells occurs, whereas desmin is responsible for keeping myofibrils in register in mature myofibers. In conclusion, the expression of nestin is dynamically orchestrated with that of vimentin and desmin during skeletal muscle regeneration and recapitulates that seen during myogenesis, i.e. these IFs have key functional roles in the construction and restoration of skeletal myofibers.

Community and occupational studies of lung cancer and polycyclic organic matter.

Finland is used as a model in attempts to study the possible association of the incidence of lung cancer and exposure of population to fossil fuel combustion products. Unfortunately because of great geographical variation of unknown origin in the incidence of lung cancer in Finland, detailed studies of the possible role of an individual exposure in the lung cancer risk are not possible. This background variation in the incidence is much greater than variation carried by any known etiological factor and does not clearly correlate with the degree of urbanization, industrialization, regional use of fossil fuels, number of motor vehicles or smoking habits. To get more precise information on the possible association of lung cancer incidence with exposure to fossil fuel combustion products, occupational studies serve as powerful tools. The definition of population is more reliable and the measurement of exposures can be done more precisely; moreover the management of confounding and modifying factors is more effective than in community studies. So far the studies carried out among the Finnish working population exposed to PAH compounds reveal an association between the lung cancer risk and exposure to PAHs.

Recent PCB accidents in Finland.

Twenty-eight polychlorinated biphenyl (PCB) accidents were recorded during a 1-year period in Finland. They comprised leaks, fires or explosions of capacitors. Some of the explosions and fires gave rise to high concentrations of PCBs in air and of PCBs and tetrachlorodibenzofurans (TCDFs), including 2,3,7,8-TCDF, on surfaces. One large explosion is described in detail, and biomedical data and findings of this case are compared with those of smaller accidents in Finland.

Incidence of occupational asthma and persistent asthma in young adults has increased in Finland.

To investigate the incidence of occupational asthma and its relationship to new cases of persistent asthma, the data was collected from two national registers which cover practically all new cases of both diseases. In 1986 to 1993, the annual incidence of persistent asthma in adults (from 15 to 64 years) increased from 6,645 to 8,056 (21%). The incidence of asthma in women increased from 3,302 to 4,717 (43%). In the age group of 15 to 29 the increase was 91%, in 30 to 49 it was 60%, and in 50 to 64 the increase was 7%. Among men, the annual incidence remained stable. However, in the age group of 15 to 29 it increased by 87%, in 30 to 49 by 46%, while a decrease of 43% was detected in the age group of 50 to 64 years. During the same period, the annual incidence of occupational asthma increased from 227 to 386 (70%), from 109 to 185 (70%) in women and from 118 to 201 (70%) in men. In 1993 the population in Finland in the age range from 15 to 64 was 2.026 million. Thus, the incidence of persistent asthma was 0.4%. The proportion of newly diagnosed occupational asthma out of all new cases of asthma was 4.8%.

In-line moisture measurement during granulation with a four-wavelength near infrared sensor: an evaluation of particle size and binder effects.

Factors affecting in-line near infrared (NIR) moisture measurement with a four-wavelength sensor were evaluated (choice of binder used in granulation liquid and the increase in particle size). An entire NIR spectrum is not necessary for the measurement of water, and often the use of only a few NIR wavelengths around the water band enables reliable and high-speed detection of moisture. Glass ballotini and microcrystalline cellulose (MCC) were used as model test materials. The binders studied were poly[1-(2-oxo-1-pyrrolidinyl)ethylene] (PVP) and gelatin. Full off-line NIR spectra of test materials at different levels of binder solutions were measured. The major spectral features for both the binders were bands around 1700 nm (first overtones CH related stretches) and 2200 nm (combination bands). Gelatin also had an NH band around 1500 nm (first overtones of NH stretches) and combination bands at about 2050 nm. Particle size effects were observed as an increase in spectra baseline. All these factors should be considered when choosing NIR wavelengths used for detection of water with a fixed wavelength set-up. A robust calibration model enables the development of in-process control of wet granulation processes.

Development and characterization of aqueous amylose-rich maize starch dispersion for film formation.

Development and characterization of amylose-rich starch dispersion for film forming was performed. The influence of dispersion preparation temperature on amylose-rich maize starch (Hylon VII) film formation, and the physical properties of the films were investigated. The film-forming ability of the dispersions was evaluated with free films plasticized with glycerol and sorbitol, and the films were prepared at an elevated temperature (70 degrees C) by a casting technique. The solid-state and particle properties of dispersions were investigated by means of X-ray diffraction (XRD), Fourier transform near infrared (FT-NIR) spectroscopy and laser diffraction particle size analysis. Free films were characterized with respect to their appearance, by FT-NIR spectroscopy, and by XRD. Mechanical stress-strain properties were also studied. Increasing the temperature of dispersion preparation results in higher crystallinity, thus affecting the film forming ability. Mechanically strong and elastic films can be formed from amylose-rich starch dispersion formed at 40 degrees C. The more crystalline precipitate complex (obtained at 80 degrees C) and the entirely amorphous gel (obtained at 10 degrees C) formed non-continuous and cloudy films. The better film-forming properties of the dispersion formed at 40 degrees C are probably due to the highly amorphous structure and smaller particle size. The study shows the possibility of using ambient tempered amylose-starch dispersion for film forming.

Novel identification of pseudopolymorphic changes of theophylline during wet granulation using near infrared spectroscopy.

The purpose of this study was to demonstrate the efficiency of near infrared (NIR) spectroscopy in studying the pseudopolymorphic changes and the state of water during the wet granulation process. Anhydrous theophylline was granulated in a planetary mixer using water as granulation liquid. NIR spectra and differential scanning calorimetric (DSC) and wide-angle X-ray scattering (WAXS) patterns of theophylline granules, anhydrous theophylline, and theophylline monohydrate were measured. At a low level of granulation liquid (0.3 mol of water per mole of anhydrous theophylline), water absorption maxima in the NIR region occurred first at around 1475 and 1970 nm. These absorption maxima were identical to those of theophylline monohydrate. At higher levels of granulation liquid (1.3-2.7 mol of water per mole of anhydrous theophylline), the increasing absorption maxima occurred at 1410 and 1905 nm due to OH vibrations of free water molecules. X-ray diffraction patterns confirmed the transformation of anhydrous theophylline to theophylline monohydrate during wet granulation. NIR spectroscopy was able to detect different states of water molecules during the wet granulation process faster and in a more flexible manner than conventional methods.

Prediction of aqueous solubility for a diverse set of organic compounds based on atom-type electrotopological state indices.

We describe robust methods for estimating the aqueous solubility of a set of 734 organic compounds from different structural classes based on multiple linear regression (MLR) and artificial neural networks (ANN) model. The structures were represented by atom-type electrotopological state (E-state) indices. The squared correlation coefficient and standard deviation for the MLR with 34 structural parameters were r(2) = 0.94 and s = 0.58 for the training set of 675 compounds. For the test set of 21 compounds, the equivalent statistics were r(2)(pred) = 0.80 and s = 0.87, respectively. Neural networks gave a significant improvement using the same set of parameters, and the standard deviations were s = 0.52 for the training set and s = 0.75 for the test set when an artificial neural network with five neurons in the hidden layer was used. The results clearly show that accurate models can be rapidly calculated for the estimation of aqueous solubility for a large and diverse set of organic compounds using easily calculated structural parameters.

The lumbar multifidus muscle five years after surgery for a lumbar intervertebral disc herniation.

Biopsy specimens of the lumbar multifidus were obtained from 18 patients with lumbar disc herniation at operation and after a postoperative follow-up period of 5 years. The structure and morphometry of the muscle fibers were analyzed and these data were compared with intraoperative biopsy results and the clinical outcome of the operation. The main findings were: 1) on the basis of occupational handicap score 10 patients belonged in the "positive" and 8 in the "negative" outcome group; 2) the intraoperatively recorded selective type 2 muscle fiber atrophy and the extent of pathologic inner structure changes both decreased in the "positive" outcome group, whereas they persisted in the "negative" group; 3) grouping as a definite sign of reinnervation was seen in only two versus four patients of the "positive" versus "negative" outcome group; 4) the relative amount of adipose tissue within the muscle decreased more markedly in the "positive" outcome group. The authors propose that both inactivity and axonal injury (mainly of neurapraxia type) contribute to the selective type 2 atrophy and inner structure changes in disc patients' multifidus muscle. These pathologic structural changes correlated well with the clinical outcome, and most importantly they are reversible and can be diminished by adequate therapy.

Rupture of the distal biceps tendon. A report of 19 patients treated with anatomic reinsertion, and a meta-analysis of 147 cases found in the literature.

We present a series of 19 avulsions of the distal tendon of the biceps brachii muscle after a follow-up of 2 to 11 years. Ten patients with delayed diagnosis and treatment (3 weeks to 5 months) were compared with nine patients treated early (within 8 days after injury). Excellent or good results at follow-up were obtained in 9 of 10 patients in the delayed-treatment group and in all 9 patients in the early-treatment group. Nine of 10 patients in the delayed-treatment group and all patients in the early-treatment group had been able to return to their preinjury levels of activity. For reference, a meta-analysis of 147 cases reported previously was performed. Ninety percent of the patients treated with an anatomic reinsertion had excellent or good results after an average follow-up of 3 years, while similar results after 3 years were seen in 60% of the patients who had nonanatomic tendon reinsertion and in 14% of the patients who were treated nonoperatively. The delay of up to 3 years between injury and anatomic reinsertion had not compromised the result. From these data we concluded that anatomic reinsertion of the avulsed distal biceps tendon to the radius is the preferred treatment in acute as well as chronic injuries.

Effects of nonsteroidal antiinflammatory medication on satellite cell proliferation during muscle regeneration.

Previous experimental studies have indicated delayed muscle regeneration after nonsteroidal antiinflammatory drug therapy. Successful regeneration of muscle after injury requires activation of normally dormant satellite cells that share the basal laminae with adjacent muscle cells. In the presence of adequate capillary ingrowth, satellite cells proliferate into myotubes and eventually form new muscle cells. In this study, the onset and extent of satellite cell and fibroblast proliferation as well as the production of myotubes and capillaries were analyzed with immunohistochemical methods after contusion injuries to rats' gastrocnemius muscles. Two groups of animals received daily doses of an intramuscular nonsteroidal antiinflammatory drug (naproxen) starting 6 hours and 3 days after injury, respectively. Treated animals were compared with similarly injured untreated animals. Satellite cell and fibroblast proliferation were unaffected by the treatment, and there were no significant differences in myotube or capillary production between treated and control animals. We conclude that naproxen treatment does not compromise the basic process of myofiber regeneration after injury.

Effects of therapeutic ultrasound on the regeneration of skeletal myofibers after experimental muscle injury.

Therapeutic ultrasound is used by many in the treatment of muscle injuries, but no previous attempts to objectively assess its effects on regenerating skeletal myofibers have been published. In this descriptive study, we followed the regeneration of contusion injury to the rat gastrocnemius muscle during treatment with pulsed ultrasound. The speed of myoregeneration in ultrasound-treated animals was compared with that in control animals by immunohistochemical, morphometric, and scintigraphic analyses. Although satellite cell proliferation was enhanced significantly (up to 96%) by the ultrasound treatment during the early stages of regeneration, there was no such effect on myotube production. The period of rapid fibroblast proliferation was extended from 3 to 4 days in the control group to 7 to 10 days in the ultrasound therapy groups, whereas recapillarization was virtually unaffected. We conclude that although treatment with pulsed ultrasound can promote the satellite cell proliferation phase of the myoregeneration, it does not seem to have significant effects on the overall morphological manifestations of muscle regeneration.

Priority setting and evaluation as tools for planning research strategy.

The growing role of research as a factor for socioeconomic development has also stimulated efforts for setting priorities and for evaluating research strategies. Priorities can be set for problems which are known for their consequences or their existing characteristics. The only way to ensure research on new problems is to allow more space for basic research aimed at revealing new data and at describing new phenomena. Evaluation methods for applied research are available, and they have been successfully used for making research units more effective and for improving the quality of the research in question.

Occupational health and safety in Finland.

The tradition of Finnish legislation on occupational health and safety began 180 years ago. The renewal cycle of the principal acts has been about 20 to 30 years. At present the Finnish occupational health and safety legislation meets the Scandinavian standard well, though the structure of the Finnish legislation meets the Scandinavian standard well, though the structure of the Finnish legislation is more fragmented. The organization and manpower resources of occupational health and safety comprise more than 100,000 persons (5% of the labor force), and the number of full-time experts is about 3,600. The finances amount to 0.3% of the gross national product. Although intensive reforms for strengthening legislation, research, and practice were carried out during the 1970s, one-third of the labor force still works under daily health and safety risks. Several occupational and nonoccupational risk consequences cummulate into one and the same high risk population. Accident risk still remains the most prevalent and severe type of risk in the Finnish work environment. Three major national programs (National Occupational Health and Safety Program, National Occupational Health Service Program and National Program for Science Policy) were established so that the needs of occupational health and safety can be met. The programs are designed to respond not only to current problems, but also to those which can be expected in the future (caused, eg, by the large-scale implementation of new technology).