Distal Gradient Research Articles

Propagating Waves in Human Motor Cortex

Previous studies in non-human primates (NHPs) have shown that beta oscillations (15–30 Hz) of local field potentials (LFPs) in the arm/hand areas of primary motor cortex (MI) propagate as traveling waves across the cortex. These waves exhibited two stereotypical features across animals and tasks: (1) The waves propagated in two dominant modal directions roughly 180° apart, and (2) their propagation speed ranged from 10 to 35 cm/s. It is, however, unknown if such cortical waves occur in the human motor cortex. This study shows that the two properties of propagating beta waves are present in MI of a tetraplegic human patient while he was instructed to perform an instruction delay center-out task using a cursor controlled by the chin. Moreover, we show that beta waves are sustained and have similar properties whether the subject was engaged in the task or at rest. The directions of the successive sustained waves both in the human subject and a NHP subject tended to switch from one dominant mode to the other, and at least in the NHP subject the estimated distance traveled between successive waves traveling into and out of the central sulcus is consistent with the hypothesis of wave reflection between the border of motor and somatosensory cortices. Further, we show that the occurrence of the beta waves is not uniquely tied to periods of increased power in the beta frequency band. These results demonstrate that traveling beta waves in MI are a general phenomenon occurring in human as well as NHPs. Consistent with the NHP data, the dominant directions of the beta LFP waves in human aligned to the proximal to distal gradient of joint representations in MI somatotopy. This consistent finding of wave propagation may imply the existence of a hardwired organization of motor cortex that mediates this spatiotemporal pattern.

Blood pressure measurement in the artery proximal and distal to an intra-arterial embolus during thrombolytic therapy

Background and aimWhen a cerebral embolism occurs, pressure gradients in the arteries between sites proximal and distal to the embolus exert hydromechanical forces that push the embolus distally, and potentially...

Phenotypic plasticity and taxonomy of Schloenbachia varians (J. Sowerby, 1817) (Cretaceous Ammonoidea)

Taxonomic concepts of Early–Middle Cenomanian representatives of Schloenbachia Neumayr, 1875 are evaluated based on well-preserved, abundant faunas from NE Iran (Atamir Formation, Koppeh Dagh) and Germany (Essen Greensand and Baddeckenstedt formations at several localities in northern Germany; Meisen Formation of Saxony). From a single Lower Cenomanian horizon in the Atamir Formation, a complete suite of specimens of Schloenbachia varians (J. Sowerby, 1817), ranging from moderately involute, compressed and finely ornamented (“forma subplana”) to more evolute, depressed and strongly spinose forms (“forma ventriosa”) with all transitional morphologies, is documented. Also in the shallow-water faunas of the “Klippenfazies” of the Essen Greensand Formation at Mulheim-Broich and of the Meisen Formation, all morphotypes co-occur. Thus, these forms cannot be regarded as geographic subspecies or successive chrono-subspecies, but reflect a high degree of variability in shell form and ornament (phenotypic plasticity) in S. varians. Interestingly, strongly tuberculate forms are rare to absent in contemporaneous offshore settings as documented by the Baddeckenstedt Formation. The phenotypic plasticity in Early Cenomanian S. varians populations is explained by ecophenotypic variation along a depth (proximal–distal) gradient: strongly tuberculate, depressed forms reflect comparatively shallow, nearshore environments with higher water energy and predation pressure, whereas compressed, weakly ornamented morphs are forms of open (and deeper) marine waters. The complete range of different forms is also observed in micro- and macroconchs, suggesting that the morphological variability is not controlled by sexual dimorphism. Based on its similarity to S. varians, also the Middle Cenomanian Ammonites coupei Brongniart, 1822 may be placed in the synonymy of the former.

Characterization of Expression in Mice of a Transgene Containing 3.3 kb of the Human Lactase-Phlorizin Hydrolase (LPH) 5′ Flanking Sequence

The regulation of human intestinal lactase-phlorizin hydrolase remains incompletely understood. One kb of pig and 2kb of rat 5'-flanking sequence controls correct tissue, cell, topographic, and villus LCT expression. To gain insight into human LCT expression, transgenic mouse lines were generated from 3.3kb of human LPH 5' flanking sequence from a lactase persistent individual fused to a human growth hormone (hGH) reporter bounded by an insulator. Four lines were identified in which reporter expression was specifically detectable in the intestine and no other organ, two of which demonstrated hGH expression specific to small and large intestine. Quantitative RT-PCR was carried out on proximal to distal segments of small intestine at fetal days 16.5 and 18.5 and at birth, postnatal days 7 and 28 in line 22. In fetal intestine, hGH expression demonstrated a proximal to distal gradient similar to that in native intestine. There was no significant difference between hGH expression levels at 7 and 28days in segment 3, the midpoint of the small intestine, where expression of endogenous lactase is maximal at 7days and declines significantly by 28days. Distal small intestine displayed high levels of hGH expression in enteroendocrine cells, which were shown to be a subset of the PYY cells. Thus, a 3.3-kb LPH 5' flanking sequence construct from a lactase persistent individual is able to maintain postnatal expression in transgenic mice post weaning.

Impaired Function of HDAC6 Slows Down Axonal Growth and Interferes with Axon Initial Segment Development

The development of morphological neuronal polarity starts by the formation and elongation of an axon. At the same time the axon initial segment (AIS) is generated and creates a diffusion barrier which differentiate axon and somatodendritic compartment. Different structural and functional proteins that contribute to the generation of neuronal action potential are concentrated at the axon initial segment. While axonal elongation is controlled by signalling pathways that regulate cytoskeleton through microtubule associated proteins and tubulin modifications, the microtubule cytoskeleton under the AIS is mostly unknown. Thus, understanding which proteins modify tubulin, where in the neuron and at which developmental stage is crucial to understanding how morphological and functional neuronal polarity is achieved. In this study performed in mice and using a well established model of murine cultured hippocampal neurons, we report that the tubulin deacetylase HDAC6 is localized at the distal region of the axon, and its inhibition with TSA or tubacin slows down axonal growth. Suppression of HDAC6 expression with HDAC6 shRNAs or expression of a non-active mutant of HDAC6 also reduces axonal length. Furthermore, HDAC6 inhibition or suppression avoids the concentration of ankyrinG and sodium channels at the axon initial segment (AIS). Moreover, treatment of mouse cultured hippocampal neurons with detergents to eliminate the soluble pool of microtubules identified a pool of detergent resistant acetylated microtubules at the AIS, not present at the rest of the axon. Inhibition or suppression of HDAC6 increases acetylation all along the axon and disrupts the specificity of AIS cytoskeleton, modifying the axonal distal gradient localization of KIF5C to a somatodendritic and axonal localization. In conclusion, our results reveal a new role of HDAC6 tubulin deacetylase as a regulator of microtubule characteristics in the axon distal region where axonal elongation takes place, and allowing the development of acetylated microtubules microdomains where HDAC6 is not concentrated, such as the axon initial segment.

The paleoredox setting of Burgess Shale-type deposits

Burgess Shale-type (BST) biotas occur globally in Lower and Middle Cambrian shales, and were preserved under specific and exceptional circumstances. Among the circumstances surrounding fossilization, benthic redox conditions have been the subject of particular disagreement. While most authors have assumed that the sites of preservation were anoxic and therefore inhospitable to metazoans, several have recently argued that BST assemblages were preserved in situ under habitable benthic conditions. Here, we use field and laboratory intensive, fine-scale methods to investigate the paleoredox settings of fossil assemblages in two Burgess Shale-type deposits, the Wheeler and Marjum Formations of western Utah (Cambrian Series 3), and review recently published data for other principal Burgess Shale-type deposits. In the Wheeler and Marjum Formations, fossil assemblages and ichnofabrics were evaluated at the millimeter scale. An ichnological model was then applied to reconstruct relative paleo-oxygen content of bottom waters at a bed-to-bed scale through multiple intervals sampled continuously. This approach permits fine-scale evaluation of the relationships of discrete fossil assemblages to paleoredox conditions. Over 7800 individual beds were logged in this study. These data demonstrate that the Wheeler and Marjum Formations were deposited under dynamic benthic redox conditions. In both deposits, beds representing deposition under dysoxic conditions may be interbedded at the millimeter–centimeter scale with those representing deposition under anoxic conditions. Although the beds deposited under both types of redox conditions may be richly fossiliferous, the distribution of fossil assemblages within the Wheeler and Marjum Formations was regulated by dissolved oxygen content of bottom waters as a first-order control. BST preservation occurs within a microfacies inferred to represent deposition under anoxic conditions, and contains transported fossils along a recognizable proximal–distal gradient. Under dysoxic benthic conditions, assemblages of skeletonized body fossils dominated by trilobites occur in both formations. In the Wheeler Formation, the junction of these two benthic redox environments is characterized by dense monospecific associations of the opportunistic trilobite Elrathia kingii, but a comparable exaerobic taxon does not appear to be present in the Marjum Formation. These results demonstrate the control of near-bottom anoxia over preservation of BST assemblages in both formations and are consistent with the findings from the Burgess Shale and the Chengjiang.

Gender Differences in the Effects of Acute Stress on Spatial Ability

Although reports that men and women differ in spatial ability are common, recent research examining stress effects on spatial navigation have not included analyses of gender differences. The current study investigated cue perception and mental rotation after an acute cold-water hand immersion stress in 156 undergraduates from the western United States. Gender differences were observed in spatial performance and spatial anxiety. Discriminant analysis revealed that distal gradient cue identification and mental rotation reaction times as well as spatial anxiety differed among men and women exposed to the acute stress and their warm-water hand immersion controls. These results indicate that stress differentially alters spatial performance in men and women, and underscores the importance of assessing gender differences when examining spatial ability.

SU-GG-T-467: Extended Gamma Criteria in Proton Patient QA Using MatrixX and MLIC

Purpose: Proton patient QA requires measurement of output and verification of range compensator for the field specific spread-out Bragg peak. Matching dose profiles and depth dose between measurement and treatment planning is desirable. Method and Materials: A calibrated detector array can measure absolute output cGy/MU, verify field shape and detect range compensator errors. Multi-Layer-Ionization-Chamber (MLIC) can measure the field's percent depth dose (PDD) without compensator. IBA MatrixX and Omnipro IMRT are used to collect and analyze profiles on three planes per patient field. Dose planes at mid SOBP, distal 90% and 50% are chosen to verify cGy/MU and field shape, steep depth gradient around field edges and thickness accuracy of the compensator, respectively. The Gamma criteria of 3 mm/3% perpendicular to the beam path are extended to along the beam direction because of the steep proton distal dose gradient. MatrixX and MLIC results are compared with PPC05's in-water measurement regarding absolute output cGy/MU and PDD, respectively. Results: For ten patient fields, the outputs of MatrixX agree with PPC05 within 2%. Shorter range compensator thickness and milling defects are detected by the 2 mm criteria along the beam path. Gamma criteria of 3 mm/3% are met on more than 98% pixels of all depths for properly milled compensators of high energy beams. Penumbra mismatches cause failure of 3 mm/3% criteria at d90 and d50 for low energy beams. This is because Eclipse does not model compensator scattering, however, 98% pixels still pass 4 mm/4% criteria. MLIC agree with PPC05 measurements within 2 mm of distal 90% range and 2% of proximal 90% range of PDD. Lower surface dose (<2% difference on the first cm) was observed between MLIC and PPC05.Conclusion: Gamma criteria are extended for proton patient QA to quantitatively measure dose matching along and perpendicular to the beam direction.

Sensorimotor cortex aspiration: A model for studying Wallerian degeneration-induced glial reactivity along the entire length of a single CNS axonal pathway

Although there are some similarities in the molecular and cellular pattern of Wallerian degeneration in the PNS and CNS, in the CNS the removal of axonal and myelin debris by microglia and astrocytes is not very efficient and occurs over a much longer time frame than seen in a peripheral nerve. Several animal models have been used to study Wallerian degeneration-induced glial reactivity in the CNS and PNS. Although these models have clarified some aspects of the mechanisms underlying the differential glial cell responses in the PNS and CNS, they do not lend themselves easily to deciphering the mechanisms governing the location and extent of Wallerian degeneration-induced CNS glial reactivity. The present study develops a new animal model that entails destruction of the left sensorimotor cortex of adult rats to induce Wallerian degeneration within the total length of a fiber tract (i.e. the dorsal corticospinal tract) that extends all the way from the cerebral cortex to the sacral level of the spinal cord. Since the axonal degeneration in the ventral medulla and dorsal funiculus of the spinal cord would be confined to the corticospinal tract, it was predicted the glial reactivity would also be restricted to this fiber tract. Three distinct proximal–distal levels of this pathway were examined to determine the morphology, distribution and immunophenotype of microglia and astrocytes between 1 day and 16 weeks after sensorimotor cortex aspiration. As expected, there was a proximal to distal gradient in the appearance of glial reactivity along the length of the pathway, with the microglial reactivity being seen as early as 3 weeks in the left pyramid, and by 4 weeks (i.e. at C6) and 6 weeks (i.e. at T11) in the right dorsal corticospinal tract. Astrocytic reactivity lagged behind that of the microglial response at each level of the pathway. The microglial and astrocytic reactivity persisted up to 16 weeks after cortical injury, which was the longest survival time studied. The sensorimotor cortex aspiration model should prove extremely useful in deciphering the molecular mechanisms controlling Wallerian degeneration-induced CNS glial reactivity and in determining the relative role of astrocytes vs microglia in clearance of axonal and myelin debris.

Distribution, development and proliferation of interstitial cells of Cajal in murine colon: an immunohistochemical study from neonatal to adult life

This paper aimed at investigating the alterations in interstitial cells of Cajal (ICC) in the proximal, middle and distal colon of mice from 0-day to 56-day post-partum (P0-P56) by immunohistochemistry. The Kit(+) ICC, which situated around myenteric nerve plexus (ICC-MY) were prominent at birth, meanwhile those cells within the smooth muscle layers (ICC-IM) and in the connective tissue beneath serosa (ICC-SS) began to appear. ICC-SM, which located at the submucosal border of circular muscle layer emerged at P6 in the proximal colon and subsequently in the distal colon at P8, and ICC in the oral side of colon revealed an earlier development in morphology and a higher density than that in the anal side. The density of ICC altered obviously during postnatal period, and the estimated total amount of ICC increased approximately 30 folds at P56 than that at P0. Some Kit(+)/Ki67(+) and Kit(+)/BrdU(+) cells were observed in ICC-MY, ICC-IM and ICC-SS, but not in ICC-SM from P0 to P24. Our result indicates a proximal to distal and transmural gradient development of ICC in the postnatal colon along with a dramatic increase of ICC cell number from neonatal to adult life, and an age-dependent proliferation of ICC is also involved.

Expression of neurotrophic factors in diabetic muscle--relation to neuropathy and muscle strength

Diabetic polyneuropathy can lead to atrophy and weakness of distally located striated muscles due to denervation. Lack of neurotrophic support is believed to contribute to the development of diabetic neuropathy. In this study, we measured the expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), neurotrophin 4 (NT-4) and ciliary neurotrophic factor (CNTF) in muscle biopsies taken from the gastrocnemic and deltoid muscles in 42 diabetic patients and 20 healthy control subjects. To express the distal neuropathic gradient and to reduce interindividual variation, a distal/proximal ratio between expression levels in the gastrocnemic and deltoid muscles was calculated for all neurotrophic factors. Neuropathic status was determined by clinical examination, electrophysiological studies and quantitative sensory examination in diabetic patients, and muscle strength at both the shoulder and ankle was assessed by isokinetic dynamometry. Distal/proximal ratios for NT-3 were lower in diabetic patients [median (range) 110.7 (39.8-546.8)] than in controls [157.6 (63.3-385.4); (P < 0.05)], and in neuropathic diabetic patients [107.1 (39.8-326.0)] versus patients without neuropathy [134.5 (46.6-546.8); (P < 0.005)]. Further, ratios for NT-3 were related to muscle strength (r(s) = 0.41, P < 0.01) and showed a tendency towards a negative relationship to the combined score of all measures of neuropathy [Neuropathy rank-sum score (NRSS)] (r(s) = -0.27, P = 0.09). Similar trends were observed for ratios for NT-4. Ratios for NGF (r(s) = -0.32, P < 0.05) and BDNF (r(s) = -0.32, P < 0.05) were related to NRSS, but not to muscle strength. Ratios for CNTF were higher in diabetic patients [64.6 (23.7-258.7)] compared with controls [50.2 (27.2-186.4); (P < 0.05)], but showed no relationship to neither NRSS nor muscle strength. Our results show that the expression of NT-3 is reduced in striated muscles in diabetic patients and is related to muscle weakness and neuropathy. We suggest that lack of NT-3 contributes to insufficient re-innervation leading to the loss of muscle strength in diabetic neuropathy.

Widespread syn‐sedimentary deformation on a muddy deep‐water basin‐floor: the Vischkuil Formation (Permian), Karoo Basin, South Africa

ABSTRACTThe ∼380‐m‐thick mudstone–siltstone‐dominated Vischkuil Formation represents the initiation phase of a 1.3‐km‐thick prograding basin floor to slope to shelf succession that marks a significant increase in the rate of siliciclastic sediment supply to the early Karoo Basin in the Permian. In the upper Vischkuil Formation three well exposed, widespread (∼3000 km2) 10–70‐m‐thick intervals of deformed strata are encased within undeformed sediments. Such chaotic mass movement deposits that are mappable over areas comparable with seismic‐scale mass transport deposits are commonly associated with submarine slope settings. However, the surrounding lithofacies and the correlation of distinctive marker beds indicate that these deformation intervals developed in a distal low gradient basin floor setting. The deformed intervals comprise a lower division of tight down‐flow verging folds dissected by thrust planes that sole out onto a highly sheared décollement surface that are interpreted as slides. The lower divisions are overlain by an upper division of chaotic lithofacies with large contorted clasts of sandstone supported by a fine‐grained matrix interpreted as a debrite. The juxtaposition of these lithofacies, the distribution of thickness of the divisions, and their close kinematic relationships indicate that the emplacement of the debris‐flows triggered and drove the underlying slide, in a low‐gradient distal setting. Individual beds in the deformed intervals can be mapped laterally into undeformed strata indicating limited movement of the slide. Therefore, widespread zones of syn‐sedimentary deformation in deep‐water settings do not necessarily indicate a slope setting and should not be used as single criterion to determine depositional setting. When associated with major debrites they may be developed on a flat basin floor.

Immunolocalisation of vasoactive intestinal peptide and substance P in the developing gut of Dicentrarchus labrax (L.).

This study was carried out on the sea bass (Dicentrarchus labrax) to follow, during development, the appearance and distribution of substance P (SP) and vasoactive intestinal peptide (VIP), which act on gut motility. The results suggest that SP and VIP play an important role as neuromodulators, influencing the motility of the digestive tract starting from the early stages of gut development, even prior to exotrophic feeding. In the peptidergic nervous system, the appearance of immunoreactivity to SP began at the rectum and followed a distal to proximal gradient, whereas for VIP, it began proximally and progressed along a proximal to distal gradient. The two peptides also appeared in gut epithelial cells. In some regions, all the cells were positive. From this distribution of positive cells, we conclude that these peptides may also have other roles, besides being neurotransmitters in the enteric nervous system and hormones of the gastro-entero-pancreatic system. VIP and SP might have paracrine and/or autocrine activity in the physiological maturation of the gut epithelium, as it has already been hypothesised for other peptides.

Energy spectrum control for modulated proton beams

In proton therapy delivered with range modulated beams, the energy spectrum of protons entering the delivery nozzle can affect the dose uniformity within the target region and the dose gradient around its periphery. For a cyclotron with a fixed extraction energy, a rangeshifter is used to change the energy but this produces increasing energy spreads for decreasing energies. This study investigated the magnitude of the effects of different energy spreads on dose uniformity and distal edge dose gradient and determined the limits for controlling the incident spectrum. A multilayer Faraday cup (MLFC) was calibrated against depth dose curves measured in water for nonmodulated beams with various incident spectra. Depth dose curves were measured in a water phantom and in a multilayer ionization chamber detector for modulated beams using different incident energy spreads. Some nozzle entrance energy spectra can produce unacceptable dose nonuniformities of up to +/-21% over the modulated region. For modulated beams and small beam ranges, the width of the distal penumbra can vary by a factor of 2.5. When the energy spread was controlled within the defined limits, the dose nonuniformity was less than +/-3%. To facilitate understanding of the results, the data were compared to the measured and Monte Carlo calculated data from a variable extraction energy synchrotron which has a narrow spectrum for all energies. Dose uniformity is only maintained within prescription limits when the energy spread is controlled. At low energies, a large spread can be beneficial for extending the energy range at which a single range modulator device can be used. An MLFC can be used as part of a feedback to provide specified energy spreads for different energies.

Coupling and propagation of normal and dysrhythmic gastric slow waves during acute hyperglycaemia in healthy humans

Acute hyperglycaemia in healthy humans disrupts slow wave rhythm similar to that observed in diabetic gastropathy, but hyperglycaemic effects on regional dysrhythmias, power, coupling and propagation are unexplored. Using mucosal mapping, we aimed to demonstrate that hyperglycaemia elicits region-specific tachygastria and evokes slow wave uncoupling between adjacent regions. Catheters with bipolar electrodes were affixed 10.5, 6 and 2 cm from the pylorus during endoscopy with midazolam in 10 healthy humans. Recordings were obtained for 1 h under basal conditions and for 1 h with hyperglycaemic clamping to 250 mg dL(-1). In basal recordings, proximal and distal slow wave frequencies were similar [2.91 +/- 0.05 vs 2.81 +/- 0.09 cycles per minute (cpm)]. Tachygastria (>3.6 cpm) was present 1.7 +/- 1.1% of the time proximally and 3.3 +/- 1.8% distally and localized to one lead 67% of the time. Proximal to distal gradients in signal power and power variability were observed. Coupling between adjacent sites was 78 +/- 2% with propagation velocities of 1.3 +/- 0.1 cm s(-1). 2 +/- 1% of segments showed >50% uncoupling. Hyperglycaemic clamping increased mean proximal (3.18 +/- 0.11 cpm) and distal (3.50 +/- 0.12 cpm) frequencies and proximal (15 +/- 6%) and distal (32 +/- 9%) tachygastria (all P < 0.01) that localized to one lead 80% of the time. During periods of normal frequency, coupling decreased proximally (54 +/- 6%) and distally (47 +/- 4%) (P < 0.01). 55 +/- 8% of segments showed >50% uncoupling (P < 0.01). In conclusion, gastric slow waves show stable, highly coupled rhythms under basal conditions. Hyperglycaemia elicits isolated tachygastrias and uncoupling of normal slow waves that are most prominent distally. These findings provide a foundation for studying slow wave conduction defects in diabetic gastropathy.

Active range of motion predicts upper extremity function 3 months after stroke.

After stroke, 80% of patients experience acute paresis of the upper extremity and only approximately one-third achieve full functional recovery. Predicting functional recovery for these patients is highly important to provide focused, cost-effective rehabilitation. Our purpose was to examine if early measures of upper extremity active range of motion (AROM) could predict recovery of upper extremity function, and to describe the trajectory of upper extremity AROM recovery over time. Thirty-three subjects were tested at 1 month and then at 3 months after stroke. Upper extremity function was measured with 6 standardized clinical tests that were synthesized into a single, sensitive score for upper extremity function using principal component analysis. The ability to move each segment (AROM) was measured using a 3-dimensional electromagnetic tracking system. Stepwise multiple regression revealed that AROM of the shoulder and middle finger segments taken at 1 month could predict 71% of the variance in upper extremity function at 3 months. All segments of the upper extremity recover similarly and no evidence of a proximal to distal gradient in motor deficits appeared over time. Simple AROM measurements of the upper extremity taken within 1 month after stroke can be used to predict upper extremity function at 3 months. This information is important for determining the prognosis of upper extremity functional recovery.

Heterogenic Feedback Between Hindlimb Extensors in the Spontaneously Locomoting Premammillary Cat

Electrophysiological studies in anesthetized animals have revealed that pathways carrying force information from Golgi tendon organs in antigravity muscles mediate widespread inhibition among other antigravity muscles in the feline hindlimb. More recent evidence in paralyzed or nonparalyzed decerebrate cats has shown that some inhibitory pathways are suppressed and separate excitatory pathways from Golgi tendon organ afferents are opened on the transition from steady force production to locomotor activity. To obtain additional insight into the functions of these pathways during locomotion, we investigated the distribution of force-dependent inhibition and excitation during spontaneous locomotion and during constant force exertion in the premammillary decerebrate cat. We used four servo-controlled stretching devices to apply controlled stretches in various combinations to the gastrocnemius muscles (G), plantaris muscle (PLAN), flexor hallucis longus muscle (FHL), and quadriceps muscles (QUADS) during treadmill stepping and the crossed-extension reflex (XER). We recorded the force responses from the same muscles and were therefore able to evaluate autogenic (intramuscular) and heterogenic (intermuscular) reflexes among this set of muscles. In previous studies using the intercollicular decerebrate cat, heterogenic inhibition among QUADS, G, FHL, and PLAN was bidirectional. During treadmill stepping, heterogenic feedback from QUADS onto G and G onto PLAN and FHL remained inhibitory and was force-dependent. However, heterogenic inhibition from PLAN and FHL onto G, and from G onto QUADS, was weaker than during the XER. We propose that pathways mediating heterogenic inhibition may remain inhibitory under some forms of locomotion on a level surface but that the strengths of these pathways change to result in a proximal to distal gradient of inhibition. The potential contributions of heterogenic inhibition to interjoint coordination and limb stability are discussed.

Intensity-modulated x-ray (IMXT) versus proton (IMPT) therapy for theragnostic hypoxia-based dose painting

In this work the abilities of intensity-modulated x-ray therapy (IMXT) and intensity-modulated proton therapy (IMPT) to deliver boosts based on theragnostic imaging were assessed. Theragnostic imaging is the use of functional or molecular imaging data for prescribing radiation dose distributions. Distal gradient tracking, an IMPT method designed for the delivery of non-uniform dose distributions, was assessed. Dose prescriptions for a hypoxic region in a head and neck squamous cell carcinoma patient were designed to either uniformly boost the region or redistribute the dose based on positron emission tomography (PET) images of the 61Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (61Cu-ATSM) hypoxia surrogate. Treatment plans for the prescriptions were created for four different delivery methods: IMXT delivered with step-and-shoot and with helical tomotherapy, and IMPT delivered with spot scanning and distal gradient tracking. IMXT and IMPT delivered comparable dose distributions within the boost region for both uniform and redistributed theragnostic boosts. Normal tissue integral dose was lower by a factor of up to 3 for IMPT relative to the IMXT. For all delivery methods, the mean dose to the nearby organs at risk changed by less than 2 Gy for redistributed versus uniform boosts. The distal gradient tracking method resulted in comparable plans to the spot scanning method while reducing the number of proton beam spots by a factor of over 3.

Absence of a proximal to distal gradient of motor deficits in the upper extremity early after stroke

Objective Our first purpose was to determine whether there was a proximal to distal gradient in motor deficits in nine segments of the affected upper extremity (shoulder, elbow, forearm, wrist, and five fingers) post-stroke. Our second purpose was to determine which upper extremity segments made the greatest contributions to hand function. Methods Thirty-three subjects were tested on average 18.6 (±5.6) days after stroke. The ability to move each segment was measured by active range of motion (AROM). Hand function was measured by a battery of standardized clinical tests which were synthesized into a single, sensitive score for hand function using principal component analysis. Results AROM at all nine segments of the upper extremity was reduced and there was no evidence of a proximal to distal gradient in AROM values. Strength of each segment was reduced and there was also no evidence of a gradient in strength values. AROM at each segment was strongly correlated with hand function scores (range 0.76–0.94). General multiple regression analysis showed that AROM explained 82% of the variance in hand function, with most of the variance shared across proximal, middle, and distal segments. Hierarchical regression analysis showed that shoulder AROM alone could explain 88% of the variance in hand function. Conclusions Early after stroke a proximal to distal gradient of motor deficits was not present, and loss of hand function was due to a loss of ability to move many segments of the upper extremity and not just the distal ones. Significance These results suggest that a change in the clinical perception of motor deficits post-stroke is needed. Our finding that shoulder AROM predicted almost all the variance in hand function opens up the possibility that this quick, simple measure may be predictive of future hand function. This would be of high economic and clinical utility compared to other ongoing efforts attempting to predict outcomes post-stroke (e.g. fMRI, MEG).

M cell development occurs preferentially in distal small intestinal Peyer's patches in mice lacking B cells (μMT), CCR6, or TRANCE/RANKL

Peyer's patches (PP) are inductive sites for generation of mucosal IgA antibody responses in the small intestine (SI). M cells are specialized epithelial cells present in the follicle‐associated epithelium (FAE) of PP that acquire small particulate antigens and convey them to immune cells in the subepithelial dome. The exact molecular signals driving differentiation of FAE enterocytes into M cells have not yet been defined. In wild type (WT) mice, the extent of M cell development is equal in PP throughout the SI. B cell deficient mice (μMT) were previously shown to have smaller PP with fewer follicles and a reduced density of M cells. Whole mount immunofluorescence staining of PP from μMT mice with Ulex europaeus lectin (UEA‐1) labeled with rhodamine reveals a consistent proximal to distal gradient in the extent of M cell development with PP follicles from the proximal third of the SI containing 6.0% of the M cells in WT PP and follicles from the distal third containing 79.0% of the WT level. A proximal to distal gradient was also observed in 2 other mutant mice (CCR6 and TRANCE/RANKL knockout mice) with impaired M cell development. In TRANCE deficient mice no M cells are observed in PP from the proximal third of the SI and the number of M cells in the middle and distal third rises to just 1.9% and 12.3% of WT levels. The existence of a proximal to distal gradient in M cell development in PP from these mutant mice demonstrates that M cell development is a complex process shaped by molecular cues that differ regionally along the SI. The greater reduction in M cells in the proximal PP of the models studied may reflect the later initiation of PP organogenesis and/or the increased density of the enteric microflora in the distal SI.Supported by the NIH (DK‐64730, DK‐64399).