Cell kinetics of vocal fold epithelium in rats.

In order to investigate the kinetics of vocal fold epithelium a bromodeoxyuridine-anti bromodeoxyuridine method has been applied in vivo at both light and electron microscopy level. This method is able to define the length of both epithelium turnover and cell-cycle in basal elements, as well as the existence of a higher proliferation rate during night time in comparison with day time. Moreover distinct labeling patterns observed in incorporating cells allow us to define the precise localization in S-phase of cycling elements.     

Motor unit recruitment strategy of knee antagonist muscles in a step-wise, increasing isometric contraction

The purpose of this study was to determine if differences exist between the control strategies of two antagonist thigh muscles during knee flexion and extension muscular coactivation. Surface myoelectric signal (MES) of the quadriceps (rectus femoris) and the hamstrings (semitendinosus) were obtained from both muscles while performing step-wise increasing contractions during flexion and extension with the knee at 1.57 rad of flexion (90 degrees). The median frequency of the power density spectrum, which is related to the average muscle fiber action potential conduction velocity and therefore to motor unit recruitment, was calculated from each MES. The results suggest that, in all the subjects tested, when the muscle acts as antagonist most motor units are recruited up to 50% of the maximal voluntary force, whereas when the muscle acts as antagonist motor units are recruited up to 40% of the maximal voluntary force. The force range past 40–50% of the maximal force is also characterized by differences between the agonist/antagonist.     

The isometric length-force models of nine different skeletal muscles.

The length-force relations of nine different skeletal muscles in the hindlimb of the cat were determined experimentally, with electrical stimulation of the sciatic nerve as the activation mode. It was shown that the active-, passive-, and total-force patterns varied widely among the muscles. The tibialis posterior (TP), medial and lateral gastrocnemius (MG, LG) and flexor digitorum longus (FDL) had a symmetric active-force curve, whereas the tibialis anterior (TA), peroneus brevis (PB), peroneus longus (PL), extensor digitorum longus (EDL), and soleus (SOL) had an asymmetric curve which exhibits about 25% of the maximal isometric force at extreme lengths. The SOL, EDL, and LG had a low-level passive force which appeared at short muscle length, whereas all other muscles exhibited initial passive force just before the optimal length. The total force was rising quasi-linearly for the SOL, whereas the other muscles exhibited an intermediate plateau about the optimal length. The LG and FDL had a substantial but temporary intermediate dip in the total force as the muscle was elongated past the optimal length. The elongation range of the various muscles also varied, ranging from +/- 15 to +/- 30% of the optimal length. The elongation range was symmetric for the FDL, LG, MG, TP, SOL, and EDL, and asymmetric for the PL, PB, and TA, being -12 to + 17%, -12 to + 17%, and -35 to + 12%, respectively. Two different models which incorporate muscle architecture were successfully fitted to the experimental data of the muscles except for the MG and TA. The architecture of these two muscles is highly nonhomogeneous and contains compartments with two pennation patterns or two different optimal lengths. New models, which add spatially and temporally the individual characteristics of each compartment of the muscles, were constructed for these two muscles. The new models demonstrated high correlation to the experimental data obtained from the MG and TA. It was concluded that the length-force relation varies widely among various skeletal muscles and is probably dependent on the primary function of the muscle in the context of integrated movement; this is a manifestation of architectural factors such as fiber pennation pattern and angle, cross-sectional area, ratio of muscle to tendon length, distribution of the fiber length within the muscle and compartmental pennation.     

Discovery and SAR of PF-4693627, a potent,selective and orally bioavailable mPGES-1 inhibitor for the potential treatment of inflammation

Inhibition of mPGES-1, the terminal enzyme in the arachidonic acid/COX pathway to regulate the production of pro-inflammatory prostaglandin PGE2, is considered an attractive new therapeutic target for safe and effective anti-inflammatory drugs. The discovery of a novel series of orally active, selective benzoxazole piperidinecarboxamides as mPGES-1 inhibitors is described. Structure–activity optimization of lead 5 with cyclohexyl carbinols resulted in compound 12, which showed excellent in vitro potency and selectivity against COX-2, and reasonable pharmacokinetic properties. Further SAR studies of the benzoxazole ring substituents lead to a novel series of highly potent compounds with improved PK profile, including 23, 26, and 29, which were effective in a carrageenan-stimulated guinea pig air pouch model of inflammation. Based on its excellent in vitro and in vivo pharmacological, pharmacokinetic and safety profile and ease of synthesis, compound 26 (PF-4693627) was advanced to clinical studies.     

Force and surface mechanomyogram frequency responses in cat gastrocnemius

Muscle surface displacement is a mechanical event taking place simultaneously with the tension generation at the tendon. The two phenomena can be studied by the surface mechanomyogram signal (MMG) (produced by a laser distance sensor) and the force signal (from a load cell). The aim of this paper was to provide data on the reliability of the laser detected MMG in muscle mechanics research. To this purpose it was verified if the laser detected MMG was suitable to estimate a frequency response in the cat medial gastrocnemius and its frequency response was compared with the one retrieved by the force signal at the tendon level. The force and MMG from the exposed medial gastrocnemius of four cats were analysed. The frequency response was investigated by sinusoidally changing the number of orderly recruited motor units, in different trials, in the 0.4-6 Hz range. It resulted that it was possible to model the force and MMG frequency response by a critically damped second-order system with two real double poles and a pure time delay. On the average, the poles were at 1.83 Hz (with 22.6 ms delay) and at 2.75 Hz (with 38 ms delay) for force and MMG, respectively. It can be concluded that MMG appears to be a reliable tool to investigate the muscle frequency response during stimulated isometric contraction. Even though not statistically significant. the differences in the second-order system parameters suggest that different components of the muscle mechanical model may specifically affect the force or MMG.     

Leptin concentration in plasma and in milk during the interpartum period in the mare

The aim of this work is to investigate on plasma profiles of leptin and estradiol 17beta during the interpartum period and leptin concentrations in the milk and in the colostrum during the period from parturition to the successive delivery in mare. Leptin plasma concentration varied from 5.1+/-2.3 ng/ml after the first parturition (week 0) to 3.0+/-0.7 at week 21 (p<0.05), then it increased to maximal level at week 49 (6.9+/-1.0 ng/ml, p<0.05). Leptin concentration in the colostrum and in the milk has been significantly (p<0.05) higher than that in plasma samples at week 1 (milk 8.8+/-2.3 versus plasma 5.2+/-0.6 ng/ml) and between week 12 and 17. This difference may be explained with a local leptin production at mammary level and supports a role of leptin in the mammary gland and/or in foal intestine. Estradiol 17beta increased from week 15 (17.9+/-2.3 pg/ml) up to 487.9+/-67.7 pg/ml at week 43. Plasma estradiol 17beta rise anticipated by 4 weeks plasma leptin increase and it does not seem to be positively correlated to leptin secretion.     

Early behavioral changes and quantitative analysis of neuropathological features in murine prion disease: Stereological analysis in the albino Swiss mice model

Behavioral and neuropathological changes have been widely investigated in murine prion disease but stereological based unbiased estimates of key neuropathological features have not been carried out. After injections of ME7 infected (ME7) or normal brain homogenates (NBH) into dorsal CA1 of albino Swiss mice and C57BL6, we assessed behavioral changes on hippocampal-dependent tasks. We also estimated by optical fractionator at 15 and 18 weeks post-injections (w.p.i.) the total number of neurons, reactive astrocytes, activated microglia and perineuronal nets (PN) in the polymorphic layer of dentate gyrus (PolDG), CA1 and septum in albino Swiss mice. On average, early behavioral changes in albino Swiss mice start four weeks later than in C57BL6. Cluster and discriminant analysis of behavioral data in albino Swiss mice revealed that four of nine subjects start to change their behavior at 12 w.p.i. and reach terminal stage at 22 w.p.i and the remaining subjects start at 22 w.p.i. and reach terminal stage at 26 w.p.i. Biotinylated dextran-amine BDA-tracer experiments in mossy fiber pathway confirmed axonal degeneration and stereological data showed that early astrocytosis, microgliosis and reduction in the perineuronal nets are independent of a change in the number of neuronal cell bodies. Statistical analysis revealed that the septal region had greater levels of neuroinflammation and extracellular matrix damage than CA1. This stereological and multivariate analysis at early stages of disease in an outbred model of prion disease provided new insights connecting behavioral changes and neuroinflammation and seems to be important to understand the mechanisms of prion disease progression.Key words: prion disease, optical fractionator, neuropathology, behavioral changes, albino Swiss mice     

Frequency-dependent changes in neuromuscular responses to cyclic lumbar flexion

Repetitive lifting in the workplace has been identified to be a cause of low back disorders. Epidemiologic data further supports an hypothesis that higher repetition rate (i.e. frequency) is an added risk factor. The objective of this study was to provide experimental data testing the above hypothesis. An in vivo feline model was subjected to 20-min of cyclic lumbar loading at frequencies of 0.1 Hz and 0.5 Hz while monitoring the EMG from the L-3/4-L-5/6 multifidus muscles and the creep at the L-4/5 level. Seven hours of rest were allowed after the cyclic flexion/extension was terminated. During this rest period, a single test cycle was performed every hour to assess recovery of EMG and lumbar creep. The results demonstrate that cyclic lumbar flexion elicits a transient neuromuscular disorder consisting of EMG spasms during the cyclic loading and initial and delayed muscular hyperexcitabilities during the rest period. Cyclic loading at 0.5 Hz resulted in significant (p<0.05) increase in the hyperexcitability magnitude and duration during the recovery period. It was concluded that repetitive lumbar loading at fast rates is indeed a risk factor as it induces larger creep in the lumbar viscoelastic tissues which in turn intensify the resulting neuromuscular disorder.