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The 137 Cs activity concentrations in moose and their principal fodder plants as well as the botanical composition of the rumen content in moose were studied in three areas of the country of Vasternorrland in Sweden. The mean 137 Cs activity concentration in moose muscle samples from the three areas with a ground deposition from 20 to 60 kBq m −2 varied between 540 and 915 Bq kg −1 . During the period July to October, three plant species — fireweed, birch and bilberry — constitute more than 70% of the rumen content. Estimation of the daily 137 Cs intake was performed based on the botanical analysis of rumen content and the 137 Cs activity concentrations found in samples of fodder plants. A mean F f of 0·19 day kg −1 was calculated. A mean aggregated transfer factor of 0·016 m 2 kg −1 was found for the three areas.

Chronic Whiplash-Associated Disorders (WAD) present with frequent pain in the neck, head and shoulder regions but the presence of frequent jaw-face pain is unclear. The aim of the study was to investigate the frequency of jaw-face pain, pain in other regions, and general symptoms in chronic WAD patients. Fifty whiplash-patients and 50 healthy age- and sex-matched controls were examined by questionnaire for pain in the jaw-face, pain in other regions and other symptoms. In contrast to healthy, a majority of the WAD patients (88%) reported frequent pain in the jaw-face, in addition to frequent pain in the neck (100%), shoulders (94%), head (90%) and back (72%). The WAD patients also reported stiffness and numbness in the jaw-face region, and frequent general symptoms such as balance problems, stress and sleep disturbances. The result suggests that frequent pain in the jaw-face can be part of the spectrum of symptoms in chronic WAD.The finding of self-reported numbness in the jaw-face indicates disturbed trigeminal nerve function and merits further investigation. We conclude that assessment of WAD should include pain in the jaw-face region. A multidisciplinary rehabilitation program including dentists, preferably specialized in the area of orofacial pain, should be advocated after whiplash injury.

The membrane lipid composition in several strains of Acholeplasma laidlawii is regulated upon a change in the growth conditions. Monoglucosyldiacylglycerol (MGlcDAG) and diglucosyldiacylglycerol (DGlcDAG) are the most abundant lipids in the A. laidlawii membrane. A third glucolipid, 3-O-acyl-monoglucosyldiacylglycerol (MAMGlcDAG) is synthesized by strain A-EF22 when the membrane lipids contain large amounts of saturated acyl chains. The lipid regulation can be understood from a simple theoretical model, in which the cells strive to maintain a balance between the lipids constituting a bilayer and those forming reversed non-lamellar liquid crystalline phases. Thus, the physical chemistry of membrane lipids, in particular their ability to form different aggregate structures, constitutes the basis for the lipid regulation, and therefore an understanding of the phase equilibria of membrane lipids is crucial. MGlcDAG and MAMGlcDAG isolated from A. laidlawii strain A-EF22 membranes were studied mainly by 2H NMR, 1H NMR, and 1H NMR diffusion measurements. MAMGlcDAG, containing 96 mol % saturated acyl chains formed a gel/crystalline phase up to about 80 degrees C, where a transition occurred to a reversed micellar (L2) phase. This is an unexpected finding for a membrane lipid. However, this lipid homogeneously mixes with the other membrane lipids at physiological temperatures. Previous and new data on MGlcDAG show that the lamellar phase is stabilized when the length and the degree of unsaturation of the acyl chains are decreased. The physicochemical properties of MAMGlcDAG and MGlcDAG were compared and found to be of great significance for the physiological regulation of the lipids in the membrane. MAMGlcDAG is synthesized under conditions when the phase equilibria of MGlcDAG are shifted from a non-lamellar toward a lamellar phase. Apart from MAMGlcDAG, MGlcDAG is the major lipid in A. laidlawii strain A-EF22 which is able to form reversed aggregate structures. MAMGlcDAG probably assists MGlcDAG in maintaining an optimal molecular packing, or negative curvature, of the lipids in the membrane.

A few cases of severe rhabdomyolysis have been reported in heart transplant recipients treated simultaneously with ciclosporin (CS) and the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor lovastatin. When measured, plasma lovastatin HMG-CoA reductase inhibitor concentrations in these patients were higher than expected. This prompted us to study the plasma concentration profiles of simvastatin HMG-CoA reductase inhibitory activity after a single dose of simvastatin in kidney transplant recipients. Five patients treated with CS, azathioprine and prednisolone (CS patients) were compared to 5 patients treated with azathioprine and prednisolone (non-CS patients). The concentration curves had similar shapes but the mean area under the curve/24 h was almost 3 times higher (p = 0.047) and the mean peak concentration was twice as high in CS patients (p = 0.028). These results suggest a difference in the disposition of simvastatin in CS patients as compared to non-CS patients. Simvastatin should be administered in a reduced dosage to CS patients.

Significant changes in extrafusal fiber type composition take place in the human masseter muscle from young age, 3-7 years, to adulthood, in parallel with jaw-face skeleton growth, changes of dentitions and improvement of jaw functions. As motor and sensory control systems of muscles are interlinked, also the intrafusal fiber population, that is, muscle spindles, should undergo age-related changes in fiber type appearance. To test this hypothesis, we examined muscle spindles in the young masseter muscle and compared the result with previous data on adult masseter spindles. Also muscle spindles in the young biceps brachii muscle were examined. The result showed that muscle spindle composition and distribution were alike in young and adult masseter. As for the adult masseter, young masseter contained exceptionally large muscle spindles, and with the highest spindle density and most complex spindles found in the deep masseter portion. Hence, contrary to our hypothesis, masseter spindles do not undergo major morphological changes between young age and adulthood. Also in the biceps, young spindles were alike adult spindles. Taken together, the results showed that human masseter and biceps muscle spindles are morphologically mature already at young age. We conclude that muscle spindles in the human young masseter and biceps precede the extrafusal fiber population in growth and maturation. This in turn suggests early reflex control and proprioceptive demands in learning and maturation of jaw motor skills. Similarly, well-developed muscle spindles in young biceps reflect early need of reflex control in learning and performing arm motor behavior.

The capillary supply and myosin heavy chain (MyHC) composition of three different intrinsic tongue muscles was analysed in the anterior and posterior regions of the human tongue with biochemical and immunohistochemical techniques. Mean capillary density for the whole tongue was 796 ± 82 cap/mm2, without regional differences. The overall number of capillaries around each fibre (CAF) was higher in the posterior than in the anterior region (2.5 vs. 2.1, p = 0.009). However, correcting for regional differences in fibre size, CAF per fibre area was higher in the anterior region (4.3 vs. 3.0, p < 0.001). Muscle fibres containing fast MyHCs predominated in the anterior region (78.7%), consisting of MyHCIIa (58.5%), MyHCIIx (1.0%), MyHCIIa+MyHCIIx (11.3%) and MyHCI+MyHCIIa (7.9%). Fibres containing slow MyHC predominated in the posterior region (65.2%), consisting of MyHCI (45.5%) and MyHCI+MyHCIIa (19.7%). A minor fibre population (

We have tested the hypothesis that leukotriene D 4 (LTD 4 ) receptor activation is involved in the development of antigen-induced bronchoconstriction. In two studies, patients with asthma received infusions of placebo or MAT-571, a potent and specific LTD 4 receptor antagonist (450 mg or 37.5 mg total dose, respectively). Antigen was inhaled during test-drug administration, and FEV 1 was measured for 10 hours after challenge. Urine samples were collected for measurement of LTE 4 ; plasma samples were drawn repeatedly for assay of MK-571. MK-571 infusions inhibited both immediate (0 to 3 hours) and late (3 to 10 hours) asthmatic responses. For the high MK-571 dose, the extent of inhibition, as assessed by the area under the curve of FEV 1 versus time was 88% ( p = 0.01) and 63% ( p = 0.01), for immediate and late responses, respectively. The low MK-571 dose also inhibited both responses but to a minor extent. Mean urinary LIE 4 excretion was elevated after antigen challenge and was unaffected by administration of the LTD 4 receptor antagonist. The present study demonstrates that MK-571 inhibits antigen-induced asthma in a dose-related fashion; it had no effect on antigen-induced increases in urinary LTE 4 excretions. The results suggest that LTD 4 receptor activation plays an important role in antigen-induced asthma.

We have investigated the reactivity of different human, rat and cat muscles to a monoclonal antibody directed against human alpha-cardiac myosin heavy chain. We have found that special fiber subpopulations of human masseter and extraocular muscles, as well as the bag fibers of human, rat and cat muscle spindles, were reactive to this antibody, indicating that these fibers expressed alpha-cardiac myosin heavy chain or a closely related isoform. This isomyosin was present in the spindle bag fibers at early fetal stages, whereas its expression in masseter and extraocular muscle fibers was not detected during the first 22 weeks of gestation. Our results add to the list of muscle proteins which are expressed in locations or at developmental stages other than those initially described, suggesting that a revision of the present nomenclature of the subgroups of myosin heavy chains might be considered in the future.

The human jaw system is different from those of other primates, carnivores, ruminants, and rodents in temporomandibular joint and muscle anatomy. In adults, jaw muscles also differ markedly from limb and trunk muscles in composition and distribution of fibre types. It can be assumed that age-related changes between young age to adulthood in terms of craniofacial growth, teeth eruption, and improvement of jaw functions are paralleled by alterations also in composition and distribution of jaw muscle fibre types. To address this question, we have examined the fibre type composition of the human masseter, a jaw closing muscle, at young age. For comparison, the young biceps brachii was examined. The results were compared with previous data for adult masseter and biceps muscles. Young masseter and biceps were similar in that type I fibres outnumbered other fibre types and were of the same diameter. However, they differed in composition of other fibre types. Young masseter contained fibre types I, IM, IIC, IIAB, IIB, and scarce IIA, with regional differences, whereas young biceps showed types I, IIA, IIAB, and few IIB. Young masseter differed from young biceps also by smaller type II fibre diameter and by containing fetal MyHC. In addition, the masseter and biceps differed in age-related changes of composition and distribution of fibre types between young age and adulthood. We conclude that the human masseter is specialized in fibre types already at young age and shows a unique fibre type growth pattern, in concordance with being a separate allotype of muscle.

The present study aimed to elucidate possible physiological mechanisms behind impaired endurance during chewing as previously reported in WAD. We tested the hypothesis of a stronger autonomic reaction in WAD than in healthy subjects in response to dynamic loading of the jaw-neck motor system.Cardiovascular reactivity, muscle fatigue indicies of EMG, and perceptions of fatigue, exhaustion and pain were assessed during standardised chewing. Twenty-one WAD subjects and a gender/age matched control group participated. Baseline recordings were followed by two sessions of alternating unilateral chewing of a bolus of gum with each session followed by a rest period.More than half of the WAD subjects terminated the test prematurely due to exhaustion and pain. In line with our hypothesis the chewing evoked an increased autonomic response in WAD exhibited as a higher increase in heart rate as compared to controls. Furthermore, we saw consistently higher values of arterial blood pressure for WAD than for controls across all stages of the experiment. Masseter EMG did not indicate muscle fatigue nor were there group differences in amplitude and mean power frequency. Pain in the WAD group increased during the first session and remained increased, whereas no pain was reported for the controls.More intense response to chewing in WAD might indicate pronounced vulnerability to dynamic loading of the jaw-neck motor system with increased autonomic reactivity to the test. Premature termination and autonomic involvement without EMG signs of muscle fatigue may indicate central mechanisms behind insufficient endurance during chewing.

Measurements of time-resolved fluorescence quenching have been performed in the binary lauroyllysophosphatidylcholine (LaLPC)/water system. The aggregation numbers, N, are determined for the micellar solution phase (N(micelle) approximately 80) and the cubic liquid crystalline I(1) phase (N(cub) approximately 90) at 298-303 K. When a quencher is present, the fluorescence decays for the hexagonal phase of the LaLPC/water system and for the bicontinuous cubic phase of monooleoylglycerol/water system are nonexponential, as expected for phase structures having long-range continuous apolar regions. Nuclear magnetic resonance (NMR) measurements of the lipid translational diffusion conclusively show that the cubic I(1) phase consists of closed micelles. NMR spectra of (31)P obtained at 202.4 MHz of this cubic phase exhibit a characteristic line shape, which is compatible with a phase structure containing short nonspherical micelles. A comparison between electron spin resonance (ESR) spin-label spectra recorded for a micellar solution and the cubic phases of the LaLPC and monooleoylglycerol systems are also shown to support a structure of closed micelles in the cubic I(1) phase of the lysolecithin system.

Eating requires mouth opening, biting, chewing and swallowing and should be performed without dysfunction or pain. Previous studies have shown that jaw opening-closing movements are the result of coordinated activation of both jaw and neck muscles, with simultaneous movements in the temporomandibular, atlanto-occipital and cervical spine joints. Consequently, it can be assumed that pain or dysfunction in any of the three joint systems involved could impair jaw activities. In fact, recent findings support this hypothesis by showing an association between neck injury and reduced amplitudes, speed and coordination of integrated jaw-neck movements. This study investigated the possible association between neck injury and disturbed eating behaviour. Fifty Whiplash-associated disorders (WAD) patients with pain and dysfunction in thejaw-face region and 50 healthy age- and sex-matched controls without any history of neck injury participated in the study. All participants were assessed by a questionnaire, which contained 26 items about eating behaviour, jaw pain and dysfunction. For the WAD group there were significant differences in jaw pain and dysfunction and eating behaviour before and after the accident, but no significant differences between WAD before and healthy. The healthy and the WAD group before the accident reported no or few symptoms. The WAD patients after the accident reported pain and dysfunction during mouth opening, biting, chewing, swallowing and yawning and felt fatigue, stiffness and numbness in the jaw-face region. In addition, a majority also reported avoiding tough food and big pieces of food, and taking breaks during meals. Altogether, these observations suggest an association between neck injury and disturbed jaw function and therefore impaired eating behaviour. A clinical implication is that examination of jaw function should be recommended as part of the assessment and rehabilitation of WAD patients.

The two dominant glucolipids in Acholeplasma laidlawii, viz., 1,2-diacyl-3-O-({alpha}-D-glucopyranosyl)-sn-glycerol (MGlcDG) and 1,2-diacyl-3-O-({alpha}-D-glucopyranosyl-(1{yields}2)-O-{alpha}-D-glucopyranosyl)-sn-glycerol (DGlcDG), have markedly different phase behavior. MGlcDG has an ability to form nonlamellar phases, whereas DGlcDG only forms lamellar phases. For maintenance of a stable lipid bilayer, the polar headgroup composition in A. laidlawii is metabolically regulated in vivo, in response to changes in the growth conditions. To investigate the mechanism behind the lipid regulation the authors have here studied bilayers of mixtures of unsaturated MGlcDG and DGlcDG, containing a small fraction of biosynthetically incorporated per-deuterated palmitic acid, with {sup 2}H NMR. The order-parameter profile of the acyl chains and an apparent transverse spin relaxation rate (R{sub 2}) were determined from dePaked quadrupole-echo spectra. The variation of order with lipid composition is rationalized from simple packing constraints. The relaxation data indicate the presence of slow reorientational motions, such as collective bilayer fluctuations and/or lipid lateral diffusion over a curved bilayer surface. The variation of acyl-chain order and bilayer curvature and/or fluctuations with sample composition are discussed in relation to the tendency of MGlcDG to form nonlamellar phases in vitro and in relation to the lipid regulation in vivo.

The results of the present study show that the early inflammatory response in plasminogen (plg)-deficient mice is not altered compared to that in wild-type (wt) mice. Therefore the chronicity of the perforation in the long-term healing experiment cannot be explained by an impairment of the early inflammatory response, but rather by an impairment in activation of the inflammatory cells. These findings give further insight into the mechanisms resulting in a clinically seen chronic tympanic membrane (TM) perforation and thus possible therapeutic strategies to replace today's conventional surgical treatment of these perforations.Plg has been shown to play an essential role in the healing of TM perforations. In plg-deficient mice a completely arrested healing reaction was seen, resulting in a chronic TM perforation. The mechanisms involved seem to be an abundant neutrophil recruitment, an accumulation of macrophages, an arrested keratinocyte migration, and a massive deposition of fibrin along the TM tissue. However, the exact functional role of plg in the early inflammatory response during healing of TM perforation remains unclear. This study aimed to evaluate the early inflammatory response, mainly the occurrence of macrophages and neutrophils, during the first 48 h following a perforation in the pars tensa (PT) of the TM, in mice lacking the plasminogen gene compared to the corresponding response in wt mice.The TMs were perforated in 45 plg-deficient and 39 wt mice. Otomicroscopic evaluation was performed at 3, 6, 9, 12, 18, 24, and 48 h after the perforation was made. Mice were harvested at all time points and prepared for morphology including immunohistochemistry (IHC). IHC was performed with antibodies targeting macrophages, neutrophils, T and B cells, cytokeratin, and fibrin(ogen). Morphometry was performed regarding the volume percentage of TM tissue occupied by the different inflammatory cells.Perforation of the TM resulted in early otomicroscopic changes of the pars flaccida (PF) in both genotypes. Infiltration of inflammatory cells to PF and the presence of edema occurred as early as 6 h after the perforation was made, in both plg-deficient and wt mice. Morphometry did not reveal any significant differences between the genotypes concerning the occurrence of inflammatory cells. In contrast to the PF, the PT showed only sparse reactions during the experimental period. Furthermore, the migration pattern of keratinocytes did not differ between the genotypes throughout the experimental period.

The purpose of the current investigation was to study the influence of sulindac and naproxen on renal function and urinary excretion of the stable hydration product of prostacyclin, 6-keto-PGF1 alpha, in patients with arthritis and impaired renal function.In a placebo-controlled, double-blind, cross-over design, the effects of 7 days of oral sulindac 200 mg twice a day were compared with naproxen 500 mg in the morning and 250 mg in the evening in 10 patients with polyarthritis and stable impaired renal function. Inulin and para-amino-hippurate sodium were used to calculate glomerular filtration rate and renal plasma flow. The excretion rate of 6-keto-PGF1 alpha was measured in urine collected overnight. After patients ingested drugs in the morning, urine was collected in fractions by spontaneous voiding. Venous blood samples were drawn repeatedly for assay of electrolytes, creatinine, proteins, hormones, and drugs. Grip strength and Ritchie articular index were recorded as indicators of symptomatic antiarthritic effectiveness.Naproxen decreased urine levels of 6-keto PGF1 alpha by 59% (p less than 0.01). Sulindac had no effect on renal prostaglandin excretion. Naproxen reduced the glomerular filtration rate and renal plasma flow by 18% (p less than 0.05) and 13% (p less than 0.05), respectively, while no significant change was observed during the sulindac treatment periods. Serum levels of creatinine and complement factor D were unaffected by either drug. Plasma renin activity decreased during naproxen and sulindac treatments by 38% (p less than 0.05) and 22% (p less than 0.05). No significant change in plasma aldosterone was observed during the two drug treatments, but urinary aldosterone declined significantly (p less than 0.05) by 34% with naproxen. Albuminuria decreased (p less than 0.05) during both naproxen (41%) and sulindac treatment (72%), while the albumin/creatinine clearance ratio decreased by 59% (p less than 0.05) only during treatment with sulindac. N-acetyl-beta-D-glucosaminidase in urine was not changed by either drug. Sulindac and naproxen had no discernible effects on base excess, excretion of water, sodium, or potassium, or on osmolal clearance. However, serum potassium increased slightly but significantly (p less than 0.01) during treatment with naproxen. Sulindac sulfide, the active metabolite of sulindac, could not be traced in the urine from any of the patients. Mean arterial blood pressure declined significantly (p less than 0.05) during sulindac treatment but did not change during treatment with naproxen. Both drugs produced equal clinical improvement as measured by grip strength and the Ritchie articular index.The results suggest that when sulindac and naproxen are given in clinical equipotent doses to patients with impaired renal function, sulindac does not affect renal prostaglandin synthesis or renal function, whereas naproxen induces suppression of renal prostaglandin synthesis and a further decrease in renal function.

ESR spectra of a paramagnetic spin probe, 5-doxylstearic acid, solubilized in the micellar and lyotropic liquid-crystalline phases of the dodecyltrimethylammonium chloride (C 12 TACl)/water system have been recorded and analyzed by employing spectral line shape simulation techniques. The partial averaging of the magnetic interactions by fast local anisotropic motions in the aggregates has been accounted for by the introduction of scaled magnetic interactions, quantified by an order matrix. The effects of aggregate rotation and amphiphile surface diffusion in phases with curved aggregated are simulated by rotational diffusion models

Quadrupolar ion NMR splittings and self-diffusion of {sup 7}Li{sup +} (I = 3/2) ions have been studied in macroscopically oriented Li-(B)DNA fibers. The {sup 7}Li splittings were measured with a double quantum filter pulse sequence, followed by subsequent fitting of the out-of-phase doublet spectrum. Lithium(I) self-diffusion was measured with the pulsed field gradient NMR spin-echo method. Diffusion was found to be restricted in both the parallel and perpendicular direction with respect to the fiber axis.

Human masticatory muscles, originating from the first branchial arch and innervated by the trigeminal nerve, have a fibre composition distinct from that of limb and trunk muscles. The zygomatic muscles, originating from the second branchial arch and innervated by the facial nerve, differ in fibre composition from either the masticatory or the limb and trunk muscles. To elucidate further the structural basis for function, and the influence of embryological origin and innervation on oro-facial muscles, the buccinator and orbicularis oris muscles, which originate from the second branchial arch and are innervated by the facial nerve, were investigated. Like the masticatory and zygomatic muscles, they have a large representation in the cerebral cortex. Both muscles were composed of type I, type IIA and a few type IIC fibres of about equal diameter. However, the type I fibres had a different myofibrillar ATPase reaction from those in masticatory, zygomatic, limb and trunk muscles; this was a moderate to strong staining at pH 9.4, indicating a special isomyosin composition. Whereas the buccinator was composed of 53% type I fibres, the orbicularis oris had a 71% predominance of type II fibres. In both muscles, the mean fibre diameter and its marked intramuscular variability were similar to earlier findings in the zygomatic muscles. No muscle spindles were found. The large number of type I fibres in the buccinator implies a capacity for endurance during continuous work at relatively low levels of force. The predominance of type II fibres in the orbicularis oris indicates that it is built up of fast-twitch motor units, related to properties such as rapid acceleration and high speed during intermittent oro-facial movements. The similarities and differences in fibre-type composition between the facial, masticatory and limb muscles imply that specific functional demands are of greater importance for muscle differentiation than embryological origin and nerve supply.

Background A computer controlled infusion pump (UIPump) for regulation of target tissue concentration of radioactive compounds was developed for use in biological research and tracer development for PET. Methods Based on observed tissue or plasma kinetics after a bolus injection of the tracer an algorithm calculates the infusion needed to obtain a specified target kinetic curve. A computer feeds this infusion scheme into an infusion pump connected to an animal via a venous catheter. The concept was validated using [11C]Flumazenil administrated to Sprague-Dawley rats where the whole brain distribution and kinetic of the tracer was measured over time using a microPET-scanner. The accuracy and precision of the system was assessed by producing steady-state levels of the tracer and by mimicking kinetics after oral administration. Results Various kinetic profiles could be generated, including rapid achievement of constant levels, or step-wise increased levels. The resulting tissue curves had low deviation from the target curves according to the specified criteria: AUC (%): 4.2 ± 2.8, Maximal deviation (%): 13.6 ± 5.0 and R2: 0.95 ± 0.02. Conclusion The UIPump-system is suitable for use in PET-research for assessment of PK/PD properties by simulation of different tracer tissue kinetics in vivo.

BACKGROUND: Clinical islet transplantation is currently being explored as a therapeutic option for persons with type I diabetes and hypoglycemic unawareness. Techniques to monitor graft survival are urgently needed to optimize the procedure. Therefore, the objective of the present study was to develop a technique for imaging survival of transplanted islets in the peritransplant and early posttransplant phase. METHODS: Isolated porcine islets were labeled in vitro with 2-deoxy-2[F]fluoro-D-glucose ([F]FDG) and infused intraportally into anesthetized pigs (n=10). Dynamic examination was performed on a positron emission tomography/computed tomography hybrid system. RESULTS: More than 95% of the radioactivity was confined to the islets at the time of transplantation. The peak percentage of infused radioactivity within the liver, quantified at the end of the islet infusion, was only 54+/-5.1%. The distribution of the radioactivity in the liver was found to be heterogeneous. A whole-body examination showed no accumulation in the lungs or brain; extrahepatic radioactivity was, except urinary excretion, evenly distributed in the pig body. CONCLUSIONS: Our results imply that almost 50% of the islets were damaged to the extent that the FDG contained was release within minutes after intraportal transplantation. The distribution of radioactivity without accumulation in the brain indicates that the activity is released from lysed islet cells in the form of [F]FDG-6P rather than native [F]FDG. The presented technique shows promise to become a powerful and quantitative tool, readily available in the clinic, to evaluate initial islet engraftment and survival.

The positron emission tomography (PET) ligand [11C]carfentanil is a selective agonist for μ-opioid receptors and has been used for studying μ-opioid receptors in the human brain. However, it is unknown if [11C]carfentanil binding differentiates between subtype receptors μ1 and μ2. In this study, we investigated whether μ1 and μ2 can be studied separately through receptor subtype–selective inhibition of [11C]carfentanil by pharmacologic intervention. [11C]Carfentanil binding characteristics on rat brain sections were assessed either alone or in the presence of the μ-receptor inhibitor cyprodime or the μ1-specific inhibitor naloxonazine. [11C]Carfentanil binding in the living rat brain was similarly studied by small animal PET/computed tomography during baseline conditions or following displacement by cyprodime or naloxonazine. Autoradiography binding studies on rat brain sections demonstrated that [11C]carfentanil has higher affinity and binding potential for μ1 than for μ2. [11C]Carfentanil binding to μ2 ...

Activated factor XI (FXIa) inhibitors are anticipated to combine anticoagulant and profibrinolytic effects with a low bleeding risk. This motivated a structure aided fragment based lead generation campaign to create novel FXIa inhibitor leads. A virtual screen, based on docking experiments, was performed to generate a FXIa targeted fragment library for an NMR screen that resulted in the identification of fragments binding in the FXIa S1 binding pocket. The neutral 6-chloro-3,4-dihydro-1H-quinolin-2-one and the weakly basic quinolin-2-amine structures are novel FXIa P1 fragments. The expansion of these fragments towards the FXIa prime side binding sites was aided by solving the X-ray structures of reported FXIa inhibitors that we found to bind in the S1-S1'-S2' FXIa binding pockets. Combining the X-ray structure information from the identified S1 binding 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment and the S1-S1'-S2' binding reference compounds enabled structure guided linking and expansion work to achieve one of the most potent and selective FXIa inhibitors reported to date, compound 13, with a FXIa IC50 of 1.0 nM. The hydrophilicity and large polar surface area of the potent S1-S1'-S2' binding FXIa inhibitors compromised permeability. Initial work to expand the 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment towards the prime side to yield molecules with less hydrophilicity shows promise to afford potent, selective and orally bioavailable compounds.

Since 1990, Merck, Sharpe & Dohme, Sweden, has created fellowships for physicians embarking upon a career in clinical pharmacology at Swedish medical schools. The fellowship has provided full salary at the level of a resident in clinical medicine for an average period of 1-2 years. Between 1992 and 2004, 22 fellows representing all six medical schools were selected for a fellowship. Of these, 20 have received specialties in clinical pharmacology, 11 now (2006) have positions as physicians in clinical pharmacology in university hospitals, 7 in the pharmaceutical industry, and 2 in a drug control agency. Two have not yet completed their training. The fellowships have been granted on the basis of excellence in clinical pharmacological problem-oriented research. The peer review of the applications has been performed by academic professors in clinical pharmacology and the chairperson of the Swedish Society of Clinical Pharmacology. The importance of having a donor with serious dedication to training and research and a scholarship organization that can prioritize these goals in an unbiased way are underlined. The Swedish MSD fellowships are a valuable complement to the resources provided by society to support the development of clinical pharmacology, i.e. the health care organizations, the faculties in medicine, and various research foundations.

We have previously introduced a new concept for natural jaw function suggesting that "functional jaw movements" are the result of coordinated jaw and neck muscle activation, leading to simultaneous movements in the temporomandibular, atlanto-occipital and cervical spine joints. Thus, jaw function requires a healthy state of both the jaw and the neck motor systems. The aim of this study was to examine the positioning of the gape in space during maximal jaw opening at fast and slow speed in healthy as well as whiplash-associated disorders (WAD) individuals. A wireless optoelectronic technique for three-dimensional movement recording was used. Subjects were seated in an upright position, with back support up to the mid-scapular level without headrest. The position of the gape in space was defined as the vertical midpoint position of the gape at maximal jaw opening (MP). In healthy, the MP generally coincided with the reference position at the start of jaw opening. In the WAD group, the MP was significantly lower than the reference position. No sex or speed related differences were found. The results suggest that both the width and orientation of the gape in space relies on coordinated jaw and neck muscle activation and mandibular and head-neck movements. This study also suggests an association between neck pain and dysfunction following trauma, and reduced width and impaired positioning of the gape in space. Finally, the MP seems to be a useful marker in evaluation of the functional state of the jaw-neck motor system.

Detection of epidermal growth factor receptor (EGFR) overexpression in many carcinomas provides important diagnostic information, which can influence patient management. The use of PET may enable such detection in vivo by a noninvasive procedure with high sensitivity. The aim of this study was to develop a method for preparation of a positron-emitting tracer based on a natural ligand to EGFR, the recombinant human epidermal growth factor (hEGF), and to perform a preclinical evaluation of the tracer.DOTA-hEGF (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) was prepared by coupling of a N-sulfosuccinimide ester of DOTA to hEGF. The conjugate was labeled with a generator-produced positron-emitting nuclide, (68)Ga (half-life = 68 min), using microwave heating. Binding specificity, affinity, internalization, and retention of (68)Ga-DOTA-hEGF was studied in 2 EGFR-expressing cell lines, U343 glioma cells and A431 cervical carcinoma cells. Biodistribution and microPET visualization studies were performed in BALB/c nu/nu mice bearing A431 carcinoma xenografts.A 1-min-long microwave-assisted labeling provided radioactivity incorporation of 77% +/- 4%. Both cell lines demonstrated receptor-specific uptake of the conjugate, rapid internalization of the tracer, and good retention of radioactivity. Binding to both cell lines occurred with high affinity, approximately 2 nmol/L. The biodistribution study demonstrated accumulation of radioactivity in xenografts and in EGFR-expressing organs. The microPET imaging study enabled visualization of tumors and demonstrated quick--within 5 min--localization of radioactivity in tumors.(68)Ga-DOTA-hEGF has potential for imaging EGFR overexpression in tumors.

Active efflux transporters in the blood-brain barrier lower the brain concentrations of many drug molecules and endogenous substances and thus affect their central action. The objective of this investigation was to study the dynamics of the entire inhibition process of the efflux transporter P-glycoprotein (P-gp), using positron emission tomography (PET). The P-gp marker [(11)C]verapamil was administered to anesthetized rats as an i.v. bolus dose followed by graded infusions via a computerized pump system to obtain a steady-state concentration of [(11)C]verapamil in brain. The P-gp modulator cyclosporin A (CsA) (3, 10 and 25 mg/kg) was administered as a short bolus injection 30 min after the start of the [(11)C]verapamil infusion. The CsA pharmacokinetics was studied in whole blood in a parallel group of rats. The CsA blood concentrations were used as input to model P-gp inhibition. The inhibition of P-gp was observed as a rapid increase in brain concentrations of [(11)C]verapamil, with a maximum after 5, 7.5 and 17.5 min for the respective doses. The respective increases in maximal [(11)C]verapamil concentrations were 1.5, 2.5 and 4 times the baseline concentration. A model in which CsA inhibited P-gp by decreasing the transport of [(11)C]verapamil out from the brain resulted in the best fit. Our data suggest that it is not the CsA concentration in blood, but rather the CsA concentration in an effect compartment, probably the endothelial cells of the blood-brain barrier that is responsible for the inhibition of P-gp.

The present study investigated potential age-related changes in human muscle spindles with respect to the intrafusal fiber-type content and myosin heavy chain (MyHC) composition in biceps brachii muscle. The total number of intrafusal fibers per spindle decreased significantly with aging, due to a significant reduction in the number of nuclear chain fibers. Nuclear chain fibers in old spindles were short and some showed novel expression of MyHC α-cardiac. The expression of MyHC α-cardiac in bag1and bag2fibers was greatly decreased in the A region. The expression of slow MyHC was increased in nuclear bag1fibers and that of fetal MyHC decreased in bag2fibers whereas the patterns of distribution of the remaining MyHC isoforms were generally not affected by aging. We conclude that aging appears to have an important impact on muscle spindle composition. These changes in muscle spindle phenotype may reflect an age-related deterioration in sensory and motor innervation and are likely to have an impact in motor control in the elderly.

We have previously shown an association between neck injury and disturbed jaw function. This study tested the hypothesis of a relationship between neck injury and impaired endurance during chewing. Fifty patients with whiplash-associated disorders (WAD) were compared with 50 temporomandibular disorders (TMD) patients and 50 healthy subjects. Endurance was evaluated during unilateral chewing of gum for 5 min when participants reported fatigue and pain. Whereas all healthy subjects completed the task, 1/4 of the TMD and a majority of the WAD patients discontinued the task. A majority of the WAD patients also reported fatigue and pain. These findings suggest an association between neck injury and reduced functional capacity of the jaw motor system. From the results, we propose that routine examination of WAD patients should include jaw function and that an endurance test as described in this study could also be a useful tool for non-dental professionals.

Coordinated mandibular and head-neck movements during jaw opening-closing activities suggest a close functional linkage between the jaw and the neck regions. The present study investigated whether size and texture of bolus can influence head-neck behavior during chewing. Using an optoelectronic 3-D recording technique, we analyzed concomitant mandibular and head-neck movements in 12 healthy adults chewing small (3 g) and large (9 g) boluses of chewing gum and Optosil®. The main finding was a head extension during chewing, the amount of which was related mainly to bolus size. Furthermore, each chewing cycle was accompanied not only by mandibular movements, but also by head extension-flexion movements. Larger head movement amplitudes were correlated with larger size and, to some extent, also with harder texture of the bolus. The results suggest that head-neck behavior during chewing is modulated in response to changes in jaw sensory-motor input.

Problem: The study investigated the early inflammatory changes in the TM in rat models of otitis media with effusion (OME), acute otitis media (AOM), and after degranulation of pars flaccida (PF) mast cells (MCs). Furthermore, we have developed a new model of AOM that resembles the natural route of infection in man. Methods: OME was initiated by blocking of the tympanal orifice of the Eustachian tube and AOM was initiated after inoculation of Streptococcus pneumoniae into the middle ear or nasal cavity. PF MCs were degranulated after local application of compound 48/80. The rats were followed-up with otomicroscopical examination. After the animals were euthanized, tympanic membranes (TMs) were dissected and embedded for (immuno-)histochemical examination. Results: OME and AOM elicited the first inflammatory response in the PF. The response to OME was discrete. During the first 48 hours of AOM the inflammatory response was intense, following a bimodal pattern. This reaction was similar to that found following MC degranulation. In AOM, macrophages predominated in PF, and polymorphonuclear cells in pars tensa. During early AOM fibrinogen/fibrin extravasated into the TM. In the new rat AOM model repeated nasal challenge with Streptococcus pneumoniae provoked AOM. Conclusion: The initial response to AOM is dependent on the activation of a nonspecific immune response that resembles that following degranulation of PF mast cells. In the OME model, the effusion may reflect a passive accumulation of fluid secreted from the normal mucosa. Fibrin deposited during early AOM may be involved in regulating the inflammatory response. Our new rat model of AOM minimizes trauma and is considered applicable to the development and testing of drugs in otitis media research. Significance: A future treatment strategy of otitis media may be transtympanic membrane treatment to modulate the early inflammatory response of the TM and middle ear cavity. Support: None reported.

The rat is a frequently used animal model for middle ear research. To date, acute otitis media (AOM) has been evoked after instillation of bacteria directly into the middle ear cavity or after traumatizing the tympanic membrane. The purpose of the study was to examine whether, with an intact tympanic membrane and middle ear cavity, intranasally deposited bacteria cause AOM and how tympanic membrane stimulation influences this procedure.In vivo, murine model.In a rat model, Streptococcus pneumoniae, type 3, was intranasally inoculated for 5 consecutive days. The tympanic membrane was treated with saline or with compound 48/80 or was left untreated. The development of AOM was evaluated by otomicroscopy, light microscopy, and middle ear culture.Ninety percent of the ears developed AOM. However, when the tympanic membranes were treated with saline or compound 48/80, only 40% and 57%, respectively, developed AOM. In all, 23 of 40 ears developed AOM and 20 ears showed growth of bacteria.Repeated intranasal deposition of S. pneumoniae, type 3, causes AOM in the rat. The development of AOM can be influenced by tympanic membrane stimulation.

In this study, we have investigated the consequences of aging on the regenerative capacity of human skeletal muscle by evaluating two parameters: (i) variation in telomere length which was used to evaluate the in vivo turn-over and (ii) the proportion of satellite cells calculated as compared to the total number of nuclei in a muscle fibre. Two skeletal muscles which have different types of innervation were analysed: the biceps brachii, a limb muscle, and the masseter, a masticatory muscle. The biopsies were obtained from two groups: young adults (23 +/- 1.15 years old) and aged adults (74 +/- 4.25 years old). Our results showed that during adult life, minimum telomere lengths and mean telomere lengths remained stable in the two muscles. The mean number of myonuclei per fibre was lower in the biceps brachii than in the masseter but no significant change was observed in either muscle with increasing age. However, the number of satellite cells, expressed as a proportion of myonuclei, decreased with age in both muscles. Therefore, normal aging of skeletal muscle in vivo is reflected by the number of satellite cells available for regeneration, but not by the mean number of myonuclei per fibre or by telomere lengths. We conclude that a decrease in regenerative capacity with age may be partially explained by a reduced availability of satellite cells.

The early inflammatory changes in the tympanic membrane were explored in 2 rat models. Acute otitis media was induced by instillation of Streptococcus pneumoniae type 3 into the middle ear cavity, and otitis media with effusion was induced by blockage of the eustachian tube. Otomicroscopic examination was performed before the rats were painlessly sacrificed at 3, 6, 9, 12, 18, 24, or 48 hours after initiation of the otitis media conditions. The tympanic membrane was studied by light and electron microscopy. Both acute otitis media and otitis media with effusion caused early inflammatory changes of the tympanic membrane, and the pars flaccida was the portion that reacted first. The inflammatory alterations were most pronounced in the acute otitis media model. The course of inflammation showed a bimodal pattern with an early deposition of a filamentous material with a band pattern, typical of fibrin. Despite a fluid-filled middle ear cavity, the inflammatory changes in the otitis media with effusion model were moderate, as was consistent with the clinical appearance of the tympanic membrane.

Although there is evidence for a reduction in breast carcinoma mortality with mammographic screening, some doubts have been expressed, and there is still uncertainty regarding the age specific effects.The authors report on a randomized, controlled trial of mammographic screening for breast carcinoma that was conducted among 51,611 women (21,650 women who were invited to a screening [the study group] and 29,961 women in a control group) ages 39-59 years in Gothenburg, Sweden. Among women in the study group, the screening interval was 18 months. The screening phase of the trial took place in 1982-1991, and follow-up for breast carcinoma mortality continued until December 31, 1996. Mortality from breast carcinoma was analyzed using a Poisson regression model. Overall and age specific effects of invitation to mammography screening on breast carcinoma mortality were calculated. Three mortality effects were estimated: the effect on deaths from breast tumors diagnosed during the screening phase of the trial, as assessed by an independent Endpoint Committee (the EPC evaluation model); the effect on deaths from breast carcinoma diagnosed during the screening phase of the trial, as determined by data from the National Cancer Registry and the National Cause of Death Register (the SCB evaluation model); and the effect on deaths from all breast carcinomas diagnosed up to December 31, 1996, as determined by the National Cancer Registry and the National Cause of Death Register (the SCB follow-up model).A nonsignificant, 21% reduction in the rate of mortality from breast carcinoma with invitation to screening was observed using the EPC evaluation model (relative risk [RR], 0.79; 95% confidence interval [95% CI], 0.58-1.08; P = 0.14); and a borderline significant, 23% rate reduction was observed using the SCB follow-up model (RR, 0.77; 95% CI, 0.60-1.00; P = 0.05). Age specific analyses yielded greater mortality rate reductions for the groups of women ages 39-44 years, 45-49 years, and 55-59 years, but there was no mortality rate reduction in the group of women ages 50-54 years. The effects of invitation to mammographic screening on the incidence of lymph node-positive disease closely paralleled the effects of invitation on breast carcinoma mortality. The effect on breast carcinoma mortality was consistent with the effect on all-cause mortality, suggesting no bias in classification of cause of death. Breast carcinoma incidence in the study group was almost identical to the incidence in the control group after trial by screening had ended in the control group (RR, 0.98; 95% CI, 0.88-1.09; P = 0.7).The current results support the commonly observed 20-30% reduction in breast carcinoma mortality with invitation to screening. The impression that screening is less effective in women younger than 50 years may be an oversimplification. Age specific effects should be a target for further research.

The muscle fibre composition of three human intrinsic tongue muscles, the longitudinalis, verticalis and transversus, was investigated in four anterior to posterior regions of the tongue using morphological and enzyme- and immunohistochemical techniques. All three muscles typically contained type I, IIA and IM/IIC fibres. Type I fibres expressed slow myosin heavy chain (MyHC), type II fibres fast MyHC, mainly fast A MyHC, whereas type IM/IIC coexpressed slow and fast MyHCs. Type II fibres were in the majority (60%), but regional differences in proportion and diameter of fibre types were obvious. The anterior region of the tongue contained a predominance of relatively small type II fibres (71%), in contrast to the posterior region which instead showed a majority of larger type I and type IM/IIC fibres (66%). In general, the fibre diameter was larger in the posterior region. This muscle fibre composition of the tongue differs from those of limb, orofacial and masticatory muscles, probably reflecting genotypic as well as phenotypic functional specialization in oral function. The predominance of type II fibres and the regional differences in fibre composition, together with intricate muscle structure, suggest generally fast and flexible actions in positioning and shaping the tongue, during vital tasks such as mastication, swallowing, respiration and speech.

Myringotomy (Myr) is one of the most frequently performed surgical procedures in children. However, events occurring in the early phases, i.e. a matter of hours, following Myr in the acute otitis media (AOM) model have not been described. The aim of the present study was to evaluate the early otomicroscopic and histopathologic reactions of the tympanic membrane (TM) after Myr during the course of AOM (AOM-Myr). The left tympanic bulla from 36 healthy Sprague-Dawley rats was inoculated with Streptococcus pneumoniae type 3. Forty-eight h later, at Day 0, 4 randomized animals were immediately sacrificed and the remaining animals were treated with bilateral Myr. Otomicroscopy and sacrifices were performed in series of 4 animals at 3, 6, 9, 12, 24 and 48 h, and 4 and 7 days. The AOM-Myr TMs were compared to non-infected Myr TMs (non-AOM-Myr). The TMs were then dissected free and routinely processed for light and electron microscopy. AOM developed in all inoculated ears at Day 0. In the pars tensa of the AOM-Myr TMs the reaction of the keratinocyte layer of the perforation border was already evident at 6 h. The lamina propria exhibited a strong inflammatory reaction, which became more organized from 12 h onwards. At Day 4 the perforations were closed in three-quarters of cases. At Day 7 all perforations were healed with a distorted scar. In the non-AOM Myr TMs a strong degranulation of mast cells and edema were found in the pars flaccida at 6 h. A keratin spur at the perforation border was not seen until 24 h. All perforations were patent on Day 7 and myringosclerotic deposits were abundant in these TMs. The infected TMs regenerated faster and closed their perforations at an earlier stage. These findings favor the hypothesis that there is a low risk of chronic perforations when myringotomizing AOM TMs.

Data on the myosin heavy chain (MyHC) composition of human muscle spindles are scarce in spite of the well-known correlation between MyHC composition and functional properties of skeletal muscle fibers. The MyHC composition of intrafusal fibers from 36 spindles of human biceps brachii muscle was studied in detail by immunocytochemistry with a large battery of antibodies. The MyHC content of isolated muscle spindles was assessed with SDS-PAGE and immunoblots. Four major MyHC isoforms (MyHCI, IIa, embryonic, and intrafusal) were detected with SDS-PAGE. Immunocytochemistry revealed very complex staining patterns for each intrafusal fiber type. The bag1 fibers contained slow tonic MyHC along their entire fiber length and MyHCI, α-cardiac, embryonic, and fetal isoforms along a variable part of their length. The bag2 fibers contained MyHC slow tonic, I, α-cardiac, embryonic, and fetal isoforms with regional variations. Chain fibers contained MyHCIIa, embryonic, and fetal isoforms throughout the fiber, and MyHCIIx at least in the juxtaequatorial region. Virtually each muscle spindle had a different allotment of numbers of bag1, bag2 and chain fibers. Taken together, the complexity in intrafusal fiber content and MyHC composition observed indicate that each muscle spindle in the human biceps has a unique identity.

PURPOSE: The NK1-receptor antagonist MK-869 (L-754,030) has demonstrated antiemetic activity in humans receiving chemotherapy. Objectives of the present trial included the first assessment of oral MK-869 plus dexamethasone compared with a 5HT3 antagonist plus dexamethasone for prevention of acute and delayed emesis after high-dose cisplatin. Furthermore, the study sought to confirm that addition of MK-869 to a 5HT3 antagonist plus dexamethasone was more effective than just the 5HT3 antagonist plus dexamethasone for prevention of acute and delayed emesis. METHODS: This multicenter, double-blind, parallel-group trial in 351 cisplatin-naïve patients evaluated prevention of acute (0 to 24 hours) and delayed emesis (primary efficacy parameter; days 2 to 5) after cisplatin (≥70 mg/m2). Patients were randomized to four groups (I to IV) (n = number randomized; number evaluable): granisetron (10 μg/kg intravenously) pre-cisplatin followed by placebo on days 2 to 5 (group I) (n = 90; 90); granisetron and MK-869 (400 mg PO [by mouth]) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group II) (n = 86; 84); MK-869 (400 mg PO) the evening before and pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group III) (n = 89; 88); or MK-869 (400 mg PO) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group IV) (n = 86; 84). All patients also received dexamethasone (20 mg PO) before cisplatin. Additional medication was available to treat emesis or nausea at any time. RESULTS: In the acute period, 57%, 80%, 46%, and 43% of patients were without emesis in groups I, II, III, and IV, respectively (P < .01 for group II v group I). In the delayed period, the proportion of patients without emesis in groups I, II, III, and IV was 29%, 63%, 51%, and 57%, respectively (P < .01 for groups II, III, and IV v group I). The distribution of nausea scores in the delayed period was lower when comparing group II with group I (P < .05 for days 1 to 5 and days 2 to 5). One serious adverse event (dizziness) was rated as possibly related to MK-869. CONCLUSION: Once daily oral administration of MK-869 was effective in reducing delayed emesis and nausea after high-dose cisplatin. However, the combination of the 5HT3 antagonist plus dexamethasone was numerically superior to MK-869 plus dexamethasone in reducing acute emesis. Confirming and extending previous findings, the triple combination of a 5HT3 antagonist, MK-869, and dexamethasone provided the best control of acute emesis.

To the Editor: Although islet transplantation is an option for patients with type 1 diabetes, even those who become insulin-independent after engraftment have islet-graft function that is estimated...

Mercuric ions are toxic to living organisms because of their strong affinity for cysteine residues in proteins. Some bacteria have developed a resistance mechanism whereby Hg2+ is transported into the cytoplasm and reduced to Hg0. One of the proteins involved in the transport of mercuric ion is the periplasmic binding protein MerP, which can exist both as oxidized (disulfide) and as reduced (dithiol) forms. Only the reduced form with Cys-17 and Cys-14 residues as free thiols is a potent receptor for mercuric ion. In this work the solution structure of the oxidized form of MerP has been determined by multidimensional NMR spectroscopy and compared to the NMR structures of the previously published structures of the reduced and mercury-bound forms of MerP. The mercury-bound and oxidized forms have similar tertiary structures, whereas in the reduced form there is a large rearrangement of the mercuric ion binding loop and the nearby loop comprising residues 38-41. The structural arrangement of the latter loop seems to be important for the stabilization of the surface location of the cysteine-containing loop. In the reduced form at low pH the cysteine-containing loop adopts a conformation similar to what is observed in the oxidized and mercury-bound forms. The oxidized form also differs with respect to the other two forms in the relative positions of some of the alpha-helices and beta-strands. Structural differences between the oxidized and reduced forms may help explain why the reduced form is stable in the periplasm, which is considered to be an oxidizing environment.

The round-window membrane (RWM) is extremely thin and is the only soft-tissue barrier between the middle ear and the inner ear. Under inflammatory conditions of the middle ear the various layers of the triple-layered RWM undergo characteristic changes parallel to the changes of the middle-ear mucosa. Several studies report that bacterial products, exo- and endotoxins, from bacteria invading the middle ear may result in profound inflammatory changes in the inner ear, followed by severe damage to the inner-ear function. The present review, in which we summarized experimental and clinical observations, on bacterial products in interactions between the middle and inner ear, focused on: 1. Bacteria and bacterial products in an inflamed middle ear that may influence inner-ear function. 2. RWM structure and RWM permeability under the influence of bacteria and bacterial products. 3. Morphological and functional inner-ear effects of bacterial infection of the middle ear, and the possible mechanisms involved. 4. Future studies to be directed in this field.

The fibre composition of functionally different regions, the superficial and the deep portions, of the human masseter and the biceps brachii muscles of six elderly subjects (mean age 74 years) was studied by morphological and enzyme-histochemical methods. When compared to previous data for young adults, the masseter muscle from elderly subjects showed a significant decrease in the proportion of type I fibres and an increase of type IM and II fibre types, concomitant with muscle fibre atrophy. In the old biceps, there were no changes in the type I fibre proportion and fibre diameter, but a significant decrease in the type IIB fibre content. The present results of changes in fibre composition, in addition to previous findings of functional deterioration of the old masseter, probably reflect a combination of age related degenerative and adaptive processes within the trigeminal neuromuscular system. When compared with previous findings in young adult masseter, it can be concluded that the human masseter muscle differs from limb muscles both in fibre composition and in structural response of the muscle during aging. These differences between the masseter and the biceps brachii muscle suggest muscle specific alterations during aging probably due to differences in genetical control, functional performance and nerve and hormonal influences.

The analysis of multidimensional neurophysiological data poses difficulties for the scientist in understanding the often complex inherent data relations. This is particularly the case when neuromuscular cell discharge parameters are to be related to body segment movement characteristics in freely behaving animals or humans. The understanding of such data is greatly simplified if the recorded data can be visualized in an adequate way, and relevant data relations are thus highlighted. This report describes a rationale for display and qualitative analyses of muscle discharge patterns in relation to three-dimensionally recorded limb or body movements. The method is illustrated by creating spatial activation plots and spatial activation maps of the electromyographic activity in the first interosseal muscle in the human hand, but this rationale for data presentation can be applied to most excitable tissues that are activated in relation to body or limb movements.

Human masseter is divided anatomical into superficial and deep parts, but regional specialisation in the distribution of fibre types and muscle spindles is organised differently. Thus, the anterior part is predominantly composed of type I fibres whereas type II fibres are concentrated in the posterior part. Spindles are most numerous and complex in the deep portion (Eriksson & Thornell, 1983; 1987). Previous studies concentrated on antero-posterior differences and were based on samples from restricted muscle regions. Since they may have missed medio-lateral variations the present study has been carried out on whole muscle transverse sections using enzyme- and immunohistochemical methods.

Immunohistochemistry was used to determine the myosin composition of defined fibre types of three embryologically different adult muscles, the oro-facial, masseter and limb muscles. In addition, the myosin composition in whole muscle specimens was analysed with biochemical methods. Both similarities and differences between muscles in the content of myosin heavy chains and myosin light chains were found. Nevertheless, each muscle had its own distinct identity. Our results indicated the presence of a previously undetected fast myosin heavy chain isoform in the oro-facial type II fibre population, tentatively termed 'fast F'. The masseter contained aberrant myosin isoforms, such as foetal myosin heavy chain and alpha-cardiac myosin heavy chain and unique combinations of myosin heavy chain isoforms which were not found in the limb or oro-facial muscles. The type IM and IIC fibres coexpressed slow and fast A myosin heavy chains in the oro-facial and limb muscles but slow and a fast B like myosin heavy chain in the masseter. While single oro-facial and limb muscle fibres contained one or two myosin heavy chain types, single masseter fibres coexpressed up to four different myosin heavy chain isoforms. Describing the fibres according to their expression of myosin heavy chain isozymes, up to five fibre types could be distinguished in the oro-facial and limb muscles and eight in the masseter. Oro-facial and limb muscles expressed five myosin light chains, MLC1S, MLC2S, MLC1F, MLC2F and MLC3F, and the masseter four, MLC1S, MLC2S, MLC1F, and, in addition, an embryonic myosin light chain, MLC1emb, which is usually not present in normal adult skeletal muscle. These results probably reflect the way the muscles have evolved to meet the specialized functional requirements imposed upon them and are in agreement with the previously proposed concept that jaw and limb muscles belong to two distinct allotypes.

An enzyme- and immunohistochemical study has been performed on human masseter muscle spindles. Antibodies selective for different myosin heavy chain (MHC) isoforms and M-band proteins (M-protein, myomesin, and MM-CK) were used. The expression of these proteins was determined in the different intrafusal fiber types. Nuclear bag1 and nuclear bag2 fibers expressed predominantly slow-twitch and slow-tonic MHCs. The bag2 fibers in addition contained fetal MHC. Nuclear chain fibers coexpressed embryonic, fetal, and fast-twitch MHCs. The bag2 and chain fibers contained all three M-band proteins, whereas the bag1 fibers contained only myomesin. In general the MHC expression in the human masseter intrafusal fiber types was similar to that previously reported for limb muscles in man as well as for limb and masseter muscles in other species. However, the number of intrafusal fibers per spindle was unusually high (up to 36). This reinforces the idea that masseter muscle spindles have a strong proprioceptive impact during the control of jaw movements. © 1994 John Wiley & Sons, Inc.

An overview of the formation and structure of lyotropic liquid crystals is given, in particular considering the influence of molecular shapes and packing constraints on the phase equilibria. Investigations of phase equilibria in phospholipid/hydrocarbon/water systems are found to be in good agreement with theoretical predictions. Aggregate structure, lipid head group hydration and counterion binding, have been studied by using nuclear magnetic resonance (NMR), electron spin resonance (ESR) and fluorescence light spectroscopy. The discussion is focused mainly on non-lamellar and cubic phases. NMR measurements of diffusion, spin relaxation and lineshape analysis can give detailed information about the structure and dynamics of cubic phases, information which is difficult to obtain by X-ray diffraction. ESR studies of micellar aggregates and vesicles are described. The ESR lineshape for some systems gives information about the size and shape of micellar aggregates. Time-resolved fluorescence spectroscopy is used to determine the aggregation number of micelles. The order and dynamics of fluorescence probes through the measurements of the fluorescence anisotropy decay are described. Finally, a discussion of electronic energy transfer in lamellar phases and lipid vesicles is given.

Background Fluorine-18 dihydrotetrabenazine [DTBZ] analogues, which selectively target the vesicular monoamine transporter 2 [VMAT2], have been extensively studied for in vivo quantification of beta cell mass by positron-emission tomography [PET]. This study describes a novel deuterated radioligand [18F]fluoroethyl [FE]-DTBZ-d4, aimed to increase the stability against in vivo defluorination previously observed for [18F]FE-DTBZ. Methods [18F]FE-DTBZ-d4 was synthesized by alkylation of 9-O-desmethyl-(+)-DTBZ precursor with deuterated [18F]FE bromide ([18F]FCD2CD2Br). Radioligand binding potential [BP] was assessed by an in vitro saturation homogenate binding assay using human endocrine and exocrine pancreatic tissues. In vivo pharmacokinetics and pharmacodynamics [PK/PD] was studied in a porcine model by PET/computed tomography, and the rate of defluorination was quantified by compartmental modeling. Results [18F]FE-DTBZ-d4 was produced in reproducible good radiochemical yield in 100 ± 20 min. Radiochemical purity of the formulated product was > 98% for up to 5 h with specific radioactivities that ranged from 192 to 529 GBq/μmol at the end of the synthesis. The in vitro BP for VMAT2 in the islet tissue was 27.0 ± 8.8, and for the exocrine tissue, 1.7 ± 1.0. The rate of in vivo defluorination was decreased significantly (kdefluorination = 0.0016 ± 0.0007 min-1) compared to the non-deuterated analogue (kdefluorination = 0.012 ± 0.002 min-1), resulting in a six fold increase in half-life stability. Conclusions [18F]FE-DTBZ-d4 has similar PK and PD properties for VMAT2 imaging as its non-deuterated analogue [18F]FE-DTBZ in addition to gaining significantly increased stability against defluorination. [18F]FE-DTBZ-d4 is a prime candidate for future preclinical and clinical studies on focal clusters of beta cells, such as in intramuscular islet grafts.