Effectiveness of a Tailored Work-Related Support Intervention for Patients Diagnosed with Gastrointestinal Cancer: A Multicenter Randomized Controlled Trial.

Purpose The aim of this research was to study the effectiveness on return to work (RTW) of an early tailored work-related support intervention in patients diagnosed with curative gastrointestinal cancer. Methods A multicenter randomized controlled trial was undertaken, in which patients were assigned randomly to the intervention or the control group (usual care). The intervention encompassed three psychosocial work-related support meetings, starting before treatment. Five self-reported questionnaires were sent over twelve months of follow-up. Primary outcome was days until RTW (fulltime or partial) and secondary outcomes included work status, quality of life, work ability, and work limitations. Descriptive analysis, Kaplan-Meier analysis, relative risk ratio and linear mixed models were applied. Results Participants (N = 88) had a mean age of 55 years; 67% were male and the most common cancer type was colon cancer (66%). Of the participants, 42 were randomized to the intervention group. The median time from sick leave until RTW was 233 days (range 187-279 days) for the control group, versus 190 days (range 139-240 days) for the intervention group (log-rank p = 0.37). The RTW rate at twelve months after baseline was 83.3% for the intervention group and 73.5% for the control group. Work limitations did statistically differ between the groups over time (p = 0.01), but quality of life and work ability did not. Conclusion Patients in the intervention group seem to take fewer days to RTW, albeit not to a statistically significant extent.Trial registration Trial NL4920 (NTR5022) (Dutch Trial Register https://www.trialregister.nl ).

Opposite effects of glucocorticoid receptor activation on hippocampal CA1 dendritic complexity in chronically stressed and handled animals.

Remodeling of synaptic networks is believed to contribute to synaptic plasticity and long-term memory performance, both of which are modulated by chronic stress. We here examined whether chronic stress modulates dendritic complexity of hippocampal CA1 pyramidal cells, under conditions of basal as well as elevated corticosteroid hormone levels. Slices were prepared from naïve, handled or chronically stressed animals and briefly treated with vehicle or corticosterone (100 nM); neurons were visualized with a fluorescent dye injected into individual CA1 pyramidal cells. We observed that 21 days of unpredictable stress did not affect hippocampal CA1 apical or basal dendritic morphology compared with naïve animals when corticosteroid levels were low. Only when slices from stressed animals were also exposed to elevated corticosteroid levels, a significant reduction in apical (but not basal) dendritic length became apparent. Unexpectedly, animals that were handled or 3 weeks showed a reduction in both apical dendritic length and number of apical branch points when compared with naïve animals. Apical dendritic length and number of branch points were restored to levels found in naïve animals several hours after in vitro treatment with 100 nM corticosterone. All effects of acute corticosterone administration could be prevented by the glucocorticoid receptor antagonist RU38486 given during the last 4 days of the stress or handling protocol. We conclude that brief exposure to high concentrations of corticosterone can differently affect apical dendritic structure, depending on the earlier history of the animal, a process that critically depends on involvement of the glucocorticoid receptor.

Acute stress increases calcium current amplitude in rat hippocampus: temporal changes in physiology and gene expression.

Activation of hippocampal glucocorticoid receptors in vitro increases calcium current amplitude through a process requiring DNA binding of receptor homodimers. We here investigated (i). whether similar increased calcium currents also occur following in vivo glucocorticoid receptor activation due to stress and (ii). if so, whether this can be explained by increased expression of calcium channel subunits. Rats were exposed to a novelty stress; some of the animals were pretreated with a glucocorticoid receptor antagonist. In subsequently prepared hippocampal slices, calcium currents were recorded from identified CA1 pyramidal neurons, after which RNA was collected, linearly amplified and hybridized with cDNA clones. Glucocorticoid receptor activation due to novelty exposure was associated with large total peak calcium currents and high-threshold noninactivating currents. Low-threshold calcium currents were not affected. Large total peak and noninactivating current amplitudes were also seen when animals received a more severe stressor, i.e. additional ether exposure. In the stressed groups, the total peak and high-threshold calcium current gradually increased with time resulting in a significant enhancement at >or=3 h after stress exposure. In the same cells, the summated (relative) RNA expression of various alpha1 calcium channel subunits was only transiently enhanced, prior to the functional changes. These data indicate that in vivo activation of glucocorticoid receptors due to stress gradually increases specific calcium current components. Prior to the functional change, increased expression of calcium channel subunits was observed, suggesting that the enhanced function could be explained by transcriptional regulation of the channels.

Changing synaptic connections on cell bodies of growing identified spinal motoneurons of the eel, Anguilla.

As the target musculature they innervate grows throughout life, certain segmental motoneurons from the spinal cord of Anguilla, readily identified on the basis of their form and position, also increase in size. In doing so, they present a steadily increasing target to the spinal and supraspinal neurons that innervate them. How the afferent neurons respond was assessed by measuring features of their synaptic boutons contacting the motoneuronal perikarya, as seen with electron microscopy. About 60% of the perimeter of the perikaryal profile of each motoneuron was found to be covered with synaptic bouton profiles, a value that is independent of the size of the motoneuron. Furthermore, the distances between synaptic profiles, their contact sizes (measured as apposition length) and the number and size of the vesicles each profile contains were all found to be relatively constant and also independent of motoneuronal size. In contrast, the number of synaptic profiles contacting a motoneuron correlated well with its perikaryal size. Our findings indicate that the challenge of a growing neuronal target is met by a steady increase in the number of contacting boutons, the form and spacing of which are held relatively constant; this strategy will require continual synaptic realignment at the target.

Long term effects of spinal cord transection in zebrafish: swimming performances, and metabolic properties of the neuromuscular system.

This study concerns functional recovery of zebrafish following spinal cord transection. Spinal cords were transected at the level of the 14th vertebra, just rostral to the dorsal fin. Recovery was tested at one month after transection when descending fibers start to regrow across the transection site and at three months after transection when fish perform kick and glide swimming. To estimate the rate of regrowth across the lesion site we analysed the tyrosine hydroxylase (TH) and dorsal 5-hydroxytryptamine (5-HT) systems in distal parts of lesioned cords. Both systems have cell bodies in the brainstem and in control fish TH- and dorsal 5-HT-containing fibers descend to all spinal segments. Swimming performance was studied by subjecting lesioned fish to endurance tests in a swimming tunnel with water flowing at a constant rate of 2 or 4.5 body lengths per second (BL/s). At 2 BL/s slow myotomal muscles are active whereas at 4.5 BL/s fast myotomal muscles are recruited. Control fish endured sustained swimming at both speeds for at least 3 hours. As a measure for the condition of the neuromuscular system in trunk and tail, we analysed aerobic metabolic capacities, assessed by NADH-tetrazolium reductase (NADH-TR) histochemistry of myotomal muscle fibers and spinal lateral neuropil. We found that TH- and dorsal 5-HT-immunoreactive fibers were absent in the entire distal part of lesioned cords at one month but at two months after transection they were present at approximately 6000 microns caudally to the site of the lesion. Thus the rate of outgrowth of these fibers is at least 200 microns per day. Sustained swimming at the slow speed (2 BL/s) could be endured for about 14.4 min at one month and for 23.5 min at two months after transection; there was no further improvement in the period that followed. In contrast, in the 10 weeks following transection, fast swimming (4.5 BL/s) could be endured for about 5 to 6 minutes. A significant improvement was gained in the period of 10 to 12 weeks after transection when fish could endure the high speed for almost 15 min. The aerobic capacity of muscle fibers in distal parts of the body was not strongly affected by the lesion. The only important change in aerobic capacity was observed in the neuropil of distal parts of the cords where, at three months after transection, NADH-TR activity was increased to approximately 150% of control values. On the basis of our findings, we assume that it is not the condition of the neuromuscular system, but rather a deficient co-ordination between proximal and distal body parts of lesioned fish that accounts for the relatively poor performances in endurance tests. Furthermore, differences in timing of improvements in swimming at 2 and 4.5 BL/s indicate that the spinal circuitries serving the slow parts of the neuromuscular system recover at an earlier stage than those serving the fast parts.

Changes in the synaptology of spinal motoneurons in zebrafish following spinal cord transection.

Effects of spinal cord transection on the synaptology of zebrafish spinal motoneurons were studied. The transection was made at the level of the 14th vertebra and the synaptology of motoneuron somata and dendrites was analysed at the level of the 21st to the 23rd vertebrae at one month and three months after transection. Horseradish peroxidase, applied to the myotomal muscle, was used to label motoneuron somata and dendritic branches in central and in lateral areas of the neuropil (referred to as central and lateral dendritic profiles). Boutons impinging on motoneurons were classified according to the morphology of the vesicles. We discerned R-boutons with spherical vesicles, F-boutons with flat vesicles and DC-boutons with at least one dense core vesicle. The apposition lengths of R-, F- and DC-boutons and the circumference of labelled profiles were determined to assess the proportional covering of boutons on somata and dendrites. Ratio's of covering with R- and F-boutons (R/F ratio) for somata, central and lateral dendritic profiles were 1.1, 2.1, and 2.1 in control fish and 0.5, 0.5 and 0.9 in lesioned fish at one month after transection, respectively. The total covering of motoneurons in lesioned fish was decreased by 20% on somata and by 30% on lateral dendritic profiles, whereas central dendritic profiles did not change significantly. At three months after transection the R/F ratio's for somata, central and lateral dendritic profiles were 0.5, 0.7 and 0.6, respectively. The total covering on somata and central and lateral dendritic profiles was at control levels. The anatomical aspects of the changes in synaptology indicate that in control fish 50 to 60% of the R-boutons on the motoneuron surface originate from descending axons. In contrast, almost all F-boutons seem to be from local origin.

Changes in size and number of spinal motoneurons in relation to growth of the musculature in the eel, Anguilla.

Estimates of the numbers of spinal motoneurones in relation to growth in the eel, Anguilla, were made by counting the axons contained within the ventral roots. Motoneuronal size was determined as the surface area of cell somata labelled retrogradely from applications of tracer (horseradish peroxidase, cobalt lysine) to the musculature or spinal nerves. The sizes and numbers of muscle fibres from red and white portions of the myotomal musculature were determined from frozen sections. Measurements of motoneurone size and number in relation to the size and number of the muscle fibres were obtained from the same body region for eels of body lengths ranging from 65 to 930 mm and for 3 different stages of the eel's life history (glass, yellow and silver eels). The mean sizes and the numbers of red and white muscle fibres, and motoneuron size, increase substantially in relation to body length; the numbers of axons in the ventral roots of fish of different body lengths, however, are very similar (approx. 130 per half segment). Silver eels are indistinguishable from yellow eels of a similar size with respect to the size and number of motoneurone somata and axons and to the number of muscle fibres. In silver eels red muscle fibres are similar in size to those of yellow eels, but the white fibres are larger.

Fusion of myocytes with larval muscle remnants during flight muscle development in the Colorado beetle.

The transformation of the slow contracting larval m. obliquus lateralis caudalis II during metamorphosis into the asynchronous indirect flight muscle, m. obliquus lateralis dorsalis, in the Colorado beetle, Leptinotarsa decemlineata, was examined by electron microscopy. Particular attention was paid to the fate of the larval muscle fibres, the origin and behaviour of the myoblasts for flight muscle development and the change of the myofibrillar filament lattice of the larva into that of the adult. In the pre-pupal period, the larval muscles dedifferentiate and fragment. At pupation, the muscle fibres consist of cell fragments containing very few myofibrils. The sarcoplasmic reticulum and the transverse tubular system are greatly reduced. The number of myoblasts developed from satellite cells by mitosis increases considerably. They penetrate the muscle fibre and surround the cell fragments. The new fibres of the flight muscle develop from myocytes fused with the larval fragments. The larval basal lamina, surrounding the cell fragments and myoblasts, is present in pupae up to 1 day old. In pupae about 2.5 days old new myofibrils appear that have the adult filament lattice. The insect muscle transformation and the repair of vertebrate muscle after injury show striking resemblances.