Issues and limitations of available biomarkers for fluoropyrimidine-based chemotherapy toxicity, a narrative review of the literature.

Fluoropyrimidine-based chemotherapies are widely used to treat gastrointestinal tract, head and neck, and breast carcinomas. Severe toxicities mostly impact rapidly dividing cell lines and can occur due to the partial or complete deficiency in dihydropyrimidine dehydrogenase (DPD) catabolism. Since April 2020, the European Medicines Agency (EMA) recommends DPD testing before any fluoropyrimidine-based treatment. Currently, different assays are used to predict DPD deficiency; the two main approaches consist of either phenotyping the enzyme activity (directly or indirectly) or genotyping the four main deficiency-related polymorphisms associated with 5-fluorouracil (5-FU) toxicity. In this review, we focused on the advantages and limitations of these diagnostic methods: direct phenotyping by evaluation of peripheral mononuclear cell DPD activity (PBMC-DPD activity), indirect phenotyping assessed by uracil levels or UH2/U ratio, and genotyping DPD of four variants directly associated with 5-FU toxicity. The risk of 5-FU toxicity increases with uracil concentration. Having a pyrimidine-related structure, 5-FU is catabolised by the same physiological pathway. By assessing uracil concentration in plasma, indirect phenotyping of DPD is then measured. With this approach, in France, a decreased 5-FU dose is systematically recommended at a uracil concentration of 16 ng/ml, which may lead to chemotherapy under-exposure as uracil concentration is a continuous variable and the association between uracil levels and DPD activity is not clear. We aim herein to describe the different available strategies developed to improve fluoropyrimidine-based chemotherapy safety, how they are implemented in routine clinical practice, and the possible relationship with inefficacy mechanisms.

Participation of ipsilateral cortical descending influences in bimanual wrist movements in humans.

There are contralateral and less studied ipsilateral (i), indirect cortical descending projections to motoneurons (MNs). We compared ipsilateral cortical descending influences on MNs of wrist flexors by applying transcranial magnetic stimulation (TMS) over the right primary motor cortex at actively maintained flexion and extension wrist positions in uni- and bimanual tasks in right-handed participants (n = 23). The iTMS response includes a short latency (~ 25 ms) motor evoked potential (iMEP), a silent period (iSP) and a long latency (~ 60 ms) facilitation called rebound (iRB). We also investigated whether the interaction between the two hands while holding an object in a bimanual task involves ipsilateral cortical descending influences. In the unimanual task, iTMS responses in the right wrist flexors were unaffected by changes in wrist position. In the bimanual task with an object, iMEPs in the right wrist flexors were larger when the ipsilateral wrist was in flexion compared to extension. Without the object, only iRB were larger when the ipsilateral wrist was extended. Thus, ipsilateral cortical descending influences on MNs were modulated only in bimanual tasks and depended on how the two hands interacted. It is concluded that the left and right cortices cooperate in bimanual tasks involving holding an object with both hands, with possible involvement of oligo- and poly-synaptic, as well as transcallosal projections to MNs. The possible involvement of spinal and transcortical stretch and cutaneous reflexes in bimanual tasks when holding an object is discussed in the context of the well-established notion that indirect, referent control underlies motor actions.

Are shallow-water shrimps proxies for hydrothermal-vent shrimps to assess the impact of deep-sea mining?

Polymetallic seafloor massive sulphide deposits are potential targets for deep-sea mining, but high concentrations of metals (including copper - Cu) may be released during exploitation activities, potentially inducing harmful impact. To determine whether shallow-water shrimp are suitable ecotoxicological proxies for deep-sea hydrothermal vent shrimp the effects of waterborne Cu exposure (3 and 10 days at 0.4 and 4 µM concentrations) in Palaemon elegans, Palaemon serratus, and Palaemon varians were compared with Mirocaris fortunata. Accumulation of Cu and a set of biomarkers were analysed. Results show different responses among congeneric species indicating that it is not appropriate to use shallow-water shrimps as ecotoxicological proxies for deep-water shrimps. During the evolutionary history of these species they were likely subject to different chemical environments which may have induced different molecular/biochemical adaptations/tolerances. Results highlight the importance of analysing effects of deep-sea mining in situ and in local species to adequately assess ecotoxicological effects under natural environmental conditions.

Functional implications of corticospinal tract impairment on gait after spinal cord injury.

OBJECTIVE: Maximum toe elevation during walking is an objective measure of foot drop and reflects the impairment of the corticospinal tract (CST) in persons with spinal cord injury (SCI). To determine if this measurement is functionally relevant to ambulatory abilities, we correlated maximum toe elevation with clinical physiotherapy tests. SETTING: Cross-sectional study, laboratory and clinical settings. METHODS: A total of 24 individuals with SCI (American Spinal Injury Association (ASIA) Impairment Scale D) were recruited. Maximum toe elevation during the swing phase of treadmill gait was measured with a kinematic system. CST function was assessed in a sitting position by measuring the motor-evoked potentials (MEPs) induced in tibialis anterior muscle with transcranial magnetic stimulation over the motor cortex. Clinical tests performed were 10-m and 6-min walk test (6MWT), Timed-Up and Go (TUG), Walking Index for Spinal Cord Injury, Berg Balance Scale, Lower Extremity Motor Score (LEMS) and sensory score of the L4, L5 and S1 dermatomes. RESULTS: Participants with lower toe elevation during gait walked at a slower speed, took more time to perform the TUG test, and covered a shorter distance in the 6MWT. They also scored lower on the LEMS and showed impaired superficial sensitivity of the dermatomes around the ankles. Few correlations were observed between CST function and clinical tests, but the presence of MEP at rest was indicative of faster speed and longer distance in the 6MWT. CONCLUSION: These results indicate that maximum toe elevation, which is directly correlated with CST impairment, is functionally relevant as it also correlates with timed clinical tests, LEMS and sensory scores.

Rapid changes in corticospinal excitability during force field adaptation of human walking.

Force field adaptation of locomotor muscle activity is one way of studying the ability of the motor control networks in the brain and spinal cord to adapt in a flexible way to changes in the environment. Here, we investigate whether the corticospinal tract is involved in this adaptation. We measured changes in motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) in the tibialis anterior (TA) muscle before, during, and after subjects adapted to a force field applied to the ankle joint during treadmill walking. When the force field assisted dorsiflexion during the swing phase of the step cycle, subjects adapted by decreasing TA EMG activity. In contrast, when the force field resisted dorsiflexion, they increased TA EMG activity. After the force field was removed, normal EMG activity gradually returned over the next 5 min of walking. TA MEPs elicited in the early swing phase of the step cycle were smaller during adaptation to the assistive force field and larger during adaptation to the resistive force field. When elicited 5 min after the force field was removed, MEPs returned to their original values. The changes in TA MEPs were larger than what could be explained by changes in background TA EMG activity. These effects seemed specific to walking, as similar changes in TA MEP were not seen when seated subjects were tested during static dorsiflexion. These observations suggest that the corticospinal tract contributes to the adaptation of walking to an external force field.

Cerebral activation is correlated to regional atrophy of the spinal cord and functional motor disability in spinal cord injured individuals.

Recovery of function following lesions in the nervous system requires adaptive changes in surviving circuitries. Here we investigate whether changes in cerebral activation are correlated to spinal cord atrophy and recovery of functionality in individuals with incomplete spinal cord injury (SCI). 19 chronic SCI individuals and 7 age-comparable controls underwent functional magnetic resonance imaging (fMRI) while performing rhythmic dorsiflexion of the ankle. A significant negative correlation was found between the activation in the ipsilateral motor (M1) and bilateral premotor cortex (PMC) on one hand and the functional ability of the SCI participants measured by the clinical motor score on the other. There was no significant correlation between activation in any other cerebral area and the motor score. Activation in ipsilateral somatosensory cortex (S1), M1 and PMC was negatively correlated to the width of the spinal cord in the left-right direction, where the corticospinal tract is located, but not in the antero-posterior direction. There was a tendency for a negative correlation between cerebral activation in ipsilateral S1, M1 and PMC and the amplitude of motor evoked potentials in the tibialis anterior muscle elicited by transcranial magnetic stimulation, but this did not reach statistical significance. There was no correlation between motor score or spinal cord dimensions and the volume of the cortical motor areas. The observations show that lesion of descending tracts in the lateral part of the spinal cord results in increased activation in ipsilateral motor and sensory areas, which may help to compensate for the functional deficit following SCI.

Independent spinal cord atrophy measures correlate to motor and sensory deficits in individuals with spinal cord injury.

STUDY DESIGN: Cross-sectional descriptive analysis of magnetic resonance imaging (MRI) and clinical outcome. OBJECTIVES: The aim of this study was to present anatomically consistent and independent spinal cord atrophy measures based on standard MRI material and analyze their specific relations to sensory and motor outcome in individuals with chronic incomplete spinal cord injury (SCI). SETTING: Danish study on human SCI. METHODS: We included 19 individuals with chronic incomplete SCI and 16 healthy controls. Participants underwent MRI and a neurological examination including sensory testing for light touch and pinprick, and muscle strength. Antero-posterior width (APW), left-right width (LRW) and cross-sectional spinal cord area (SCA) were extracted from MRI at the spinal level of C2. The angular variation of the spinal cord radius over the full circle was also extracted and compared with the clinical scores. RESULTS: The motor score was correlated to LRW and the sensory scores were correlated to APW. The scores correlated also well with decreases in spinal cord radius in oblique angles in coherent and non-overlapping sectors for the sensory and motor qualities respectively. CONCLUSION: APW and LRW can be used to assess sensory and motor function independently. The finding is corresponding well with the respective locations of the main sensory and motor pathways.

A dynamic model of plant growth with interactions between development and functional mechanisms to study plant structural plasticity related to trophic competition.

BACKGROUND AND AIMS: The strong influence of environment and functioning on plant organogenesis has been well documented by botanists but is poorly reproduced in most functional-structural models. In this context, a model of interactions is proposed between plant organogenesis and plant functional mechanisms. METHODS: The GreenLab model derived from AMAP models was used. Organogenetic rules give the plant architecture, which defines an interconnected network of organs. The plant is considered as a collection of interacting 'sinks' that compete for the allocation of photosynthates coming from 'sources'. A single variable characteristic of the balance between sources and sinks during plant growth controls different events in plant development, such as the number of branches or the fruit load. KEY RESULTS: Variations in the environmental parameters related to light and density induce changes in plant morphogenesis. Architecture appears as the dynamic result of this balance, and plant plasticity expresses itself very simply at different levels: appearance of branches and reiteration, number of organs, fructification and adaptation of ecophysiological characteristics. CONCLUSIONS: The modelling framework serves as a tool for theoretical botany to explore the emergence of specific morphological and architectural patterns and can help to understand plant phenotypic plasticity and its strategy in response to environmental changes.

Characteristics and mechanisms of locomotion induced by intraspinal microstimulation and dorsal root stimulation in spinal cats.

Intraspinal microstimulation (ISMS) through a single microelectrode can induce locomotion in cats spinalized at T(13) 1 wk before (untrained) or after 3-5 wk of treadmill training. Here we study the optimal parameters of ISMS and the characteristics of locomotion evoked. ISMS was applied in the dorsal region of segments L(3)-S(1) at different lateralities (midline to 2.5 mm) and after an intravenous injection of clonidine (noradrenergic agonist). Kinematics and electromyographic recordings were used to characterize locomotion. ISMS could induce a bilateral locomotor pattern similar to that obtained with perineal stimulation, and the characteristics of locomotion varied according to the spinal segment stimulated. Mechanisms by which ISMS could evoke locomotion were then investigated by stimulating, inactivating, or lesioning different spinal structures. Dorsal root stimulation (DRS), just like ISMS, could evoke a variety of ipsi- and bilateral nonlocomotor movements as well as locomotor responses. This suggests that sensory afferent pathways are involved in the production of locomotion by ISMS. Microinjections of yohimbine (noradrenergic antagonist) in L(3) and L(4) segments or a complete second spinal lesion at L(3)-L(4) abolished all locomotor activity evoked by ISMS applied at more caudal segments. Progressive dorsoventral spinal lesions at L(3) or L(4) and restricted ventral lesions at L(4) further suggest that the integrity of the ventral or ventrolateral funiculi as well as the L(3)-L(4) segments are critical for the induction of locomotion by ISMS at L(5) to S(1) or by DRS at these caudal segments.

Relative extents of preformation and neoformation in tree shoots: Analysis by a deconvolution method.

BACKGROUND AND AIMS: Neoformation is the process by which organs not preformed in a bud are developed on a growing shoot, generally after preformation extension. The study of neoformation in trees has been hindered due to methodological reasons. The present report is aimed at assessing the relative importance of preformation and neoformation in the development of shoots of woody species. METHODS: A deconvolution method was applied to estimate the distribution of the number of neoformed organs for eight data sets corresponding to four Nothofagus species and a Juglans hybrid. KEY RESULTS: The number of preformed organs was higher and less variable than the number of neoformed organs. Neoformation contributed more than preformation to explain full-size differences between shoots developed in different positions within the architecture of each tree species. CONCLUSIONS: Differences between the distributions of the numbers of preformed and neoformed organs may be explained by alluding to the duration of differentiation and extension for each of these groups of organs. The deconvolution of distributions is a useful tool for the analysis of neoformation and shoot structure in trees.

Adaptive changes of locomotion after central and peripheral lesions.

This paper reviews findings on the adaptive changes of locomotion in cats after spinal cord or peripheral nerve lesions. From the results obtained after lesions of the ventral/ventrolateral pathways or the dorsal/dorsolateral pathways, we conclude that with extensive but partial spinal lesions, cats can regain voluntary quadrupedal locomotion on a treadmill. Although tract-specific deficits remain after such lesions, intact descending tracts can compensate for the lesioned tracts and access the spinal network to generate voluntary locomotion. Such neuroplasticity of locomotor control mechanisms is also demonstrated after peripheral nerve lesions in cats with intact or lesioned spinal cords. Some models have shown that recovery from such peripheral nerve lesions probably involves changes at the supra spinal and spinal levels. In the case of somesthesic denervation of the hindpaws, we demonstrated that cats with a complete spinal section need some cutaneous inputs to walk with a plantigrade locomotion, and that even in this spinal state, cats can adapt their locomotion to partial cutaneous denervation. Altogether, these results suggest that there is significant plasticity in spinal and supraspinal locomotor controls to justify the beneficial effects of early proactive and sustained locomotor training after central (Rossignol and Barbeau 1995; Barbeau et al. 1998) or peripheral lesions.

Axis differentiation in two South American Nothofagus species (Nothofagaceae).

An analysis was carried out on the length, diameter and number of leaves, and the ratios between these variables for current-year growth units (sibling growth units) derived from different nodes of previous-year growth units (parent growth units) of young Nothofagus dombeyi and Nothofagus pumilio trees. Changes in sibling growth unit length, diameter, and number of leaves with position on the parent growth unit were assessed. In both species, sibling-growth unit morphology varied according to both the axis type of the parent growth unit and the position of the sibling growth unit on its parent growth unit. For the largest parent growth units, the length, diameter and number of leaves of their sibling growth units decreased from distal to proximal positions on the parent growth unit. Distal sibling growth units had a more slender stem and longer internodes than proximal sibling growth units. Sibling growth units in equivalent positions tended to have a more slender stem for N. dombeyi than for N. pumilio. Long main-branch growth units of N. pumilio had longer internodes than those of N. dombeyi; the converse was true for shorter growth units. The growth unit diameter/leaf number ratio was consistently higher for N. pumilio than for N. dombeyi. Nothofagus pumilio axes would go through a faster transition from an 'exploring' morphology to an 'exploiting' morphology than N. dombeyi axes. Within- and between-species variations in growth unit morphology should be considered when assessing the adaptive value of the branching pattern of plants.

Periods of organogenesis in mono- and bicyclic annual shoots of Juglans regia L. (Juglandaceae).

The organogenetic cycle of shoots on main branches of 4-year-old Juglans regia trees was studied. Mono- and bicyclic floriferous and vegetative annual shoots were analysed. Five parent annual shoot types were sampled between October 1992 and August 1993. Organogenesis of summer growth units was monitored between 16 Jun. and 3 Aug. 1993. Variations over time in the number of nodes, cataphylls and embryonic green leaves of terminal buds were studied. The number of nodes of parent shoot buds was compared with the number of nodes of shoots derived from parent shoot buds. The spring growth units of mono- and bicyclic shoots consist exclusively of preformed leaves which were differentiated, respectively, during the spring flush of growth (mid-April until mid-May) or the summer flush of growth (mid-June until early August) in the previous growing season. Thus, winter buds may consist of flower and leaf primordia differentiated in two different periods during annual shoot extension. The summer growth units of bicyclic shoots consist of preformed leaves that were differentiated in spring buds during the spring flush of growth in the current growing season. Bud morphology is compared between spring and summer shoots.

Periods of organogenesis in shoots of Nothofagus dombeyi (Mirb.) oersted (Nothofagaceae).

The organogenetic cycle of main-branch shoots of Nothofagus dombeyi (Nothofagaceae) was studied. Twelve samples of 52-59 parent shoots were collected from a roadside population between September 1999 and October 2000. Variations over time in the number of nodes of terminal and axillary buds, and the length, diameter and number of leaves of shoots derived from these buds (sibling shoots) were analysed. The number of nodes of buds developed by parent shoots was compared with the number of nodes of buds developed, I year later, by sibling shoots. The length, diameter and number of leaves of sibling shoots increased from October 1999 to February 2000 in those shoots with a terminal bud. However, extension of most sibling shoots, including the first five most distal leaf primordia, ceased before February due to abscission of the shoot apex. Axillary buds located most distally on a shoot had more nodes than both terminal buds and more proximal axillary buds. The longest shoots included a preformed part and a neoformed part. The organogenetic event which initiated the neoformed organs continued until early autumn, giving rise to the following year's preformation. The absence of cataphylls in terminal buds could indicate a low intensity of shoot rest. The naked terminal bud of Nothofagus spp. could be interpreted as a structure less specialized than the scaled bud found in genera of Fagaceae and Betulaceae.

Preformation and neoformation in shoots of Nothofagus antarctica (G. Forster) Oerst. (Nothofagaceae) shrubs from northern Patagonia.

The size (length and diameter) and number of leaf primordia of winter buds of Nothofagus antarctica (G. Forster) Oerst. shrubs were compared with the size and number of leaves of shoots derived from buds in equivalent positions. Buds developed in two successive years were compared in terms of size and number of leaf primordia. Bud size and the number of leaf primordia per bud were greater for distal than for proximally positioned buds. Shoots that developed in the five positions closest to the distal end of their parent shoots had significantly more leaves than more proximally positioned shoots of the same parent shoots. The positive relationship between the size of a shoot and that of its parent shoot was stronger for proximal than for distal positions on the parent shoots. For each bud position on the parent shoots there were differences in the number of leaf primordia per bud between consecutive years. The correlations between the number of leaf primordia per bud and bud size, bud position and parent shoot size varied between years. Only shoots produced close to the distal end of a parent shoot developed neoformed leaves; more proximal sibling shoots consisted entirely of preformed leaves. Leaf neoformation, a process usually linked with high shoot vigour in woody plants, seems to be widespread among the relatively small shoots developed in N. antarctica shrubs, which may relate to the species' opportunistic response to disturbance.

Recovery of locomotion in the cat following spinal cord lesions.

In most species, locomotor function beneath the level of a spinal cord lesion can be restored even if the cord is completely transected. This suggests that there is, within the spinal cord, an autonomous network of neurons capable of generating a locomotor pattern independently of supraspinal inputs. Recent studies suggest that several physiological and neurochemical changes have to occur in the neuronal networks located caudally to the lesion to allow the expression of spinal locomotion. Some evidence of this plasticity will be addressed in this review. In addition, original data on the functional organisation of the lumbar spinal cord will also be presented. Recent works in our lab show that segmental responsiveness of the spinal cord of the cat to locally micro-injected drugs in different lumbar segments, in combination with complete lesions at various level of the spinal cord, suggest a rostro-caudal organisation of spinal locomotor control. Moreover, the integrity of midlumbar segments seems to be crucial for the expression of spinal locomotion. These data suggest that the regions of critical importance for locomotion can be confined to a restricted portion of the spinal cord. Later, these midlumbar segments could be targeted by electrical stimulation or grafts to improve recovery of function. Understanding the changes in spinal cord neurophysiology and neurochemistry after a lesion is of critical importance to the improvement of treatments for locomotor rehabilitation in spinal-cord-injured patients.

Pattern analysis in branching and axillary flowering sequences.

In the architectural approach to the study of plants, a major issue is to analyse branching and axillary flowering patterns. Due to the structured expression of the branching process and the noisy character of the observed patterns, we propose an analysis framework which is both structural and probabilistic. Data take the form of sequences which naturally represent the underlying structural information of branching and axillary flowering patterns and allow the application of a large number of methods ranging from exploratory analysis to stochastic modeling. The primary aim of the proposed analysis methods is to reveal patterns not directly apparent in the data, and thus to deepen our biological understanding of the underlying mechanisms that control the branching and the axillary flowering of plants over time and space. The proposed approach is illustrated using a set of examples corresponding to different plant species and different biological or agronomic objectives.

The development of vesicular acetylcholine transporter immunoreactivity in the hindlimbs of the opossum Monodelphis domestica.

Vesicular acetylcholine transporter (VAChT) was revealed immunohistochemically in light microscopy on hindlimb sections of developing opossums, Monodelphis domestica. In the immobile hindlimbs of the newborn, which comprise cartilaginous bones and loose, unstriated myofibers, scant immunolabeled nerve segments and small spherical terminals, presumably growth cones or immature neuromuscular junctions, are found in the muscle tissue of the thigh, leg and proximal foot, decreasing in number and size proximodistally. When the hindlimbs start moving at 1 week, terminals are more numerous and larger, still decreasing proximodistally, and occur in the newly formed interosseous foot muscles. At 4 weeks, when the hindlimbs start supporting weight and quadrupedal locomotion appears, terminals are more numerous, flattened and in comparable size and density in thigh, leg and foot muscles. By 7 weeks, large and completely flat terminals are observed in groups of 3 to 4 at regular intervals along muscle fibers. VAChT expression develops largely postnatally in the opossum hindlimbs, along a proximodistal gradient that parallels somatic and reflex development.

Dioecy in Fitzroya cupressoides (Molina) I.M. Johnst. and Pilgerodendron uviferum (D. Don.) Florin (Cupressaceae).

The aim of this study was to determine the dioecious or monoecious condition of Fitzroya cupressoides and Pilgerodendron uviferum. The study area lies west of the Nahuel Huapi National Park in northern Patagonia (Argentina), where these species form mixed stands. One hundred individuals of each species were studied over three successive years. The nature and position in the crown of their reproductive organs were recorded. Results showed that both species are dioecious. This feature has been confirmed on trees of these species growing in other sites within their natural distribution area in Argentina and Chile.