Upper limb motor dysfunction is associated with fragmented kinetics after brain injury.

BACKGROUND: Characterization of motor deficits after brain injury is important for rehabilitation personalization. While studies reported abnormalities in the kinematics of paretic and non-paretic elbow extension for patients with brain injuries, kinematic analysis is not sufficient to explore how patients deal with musculoskeletal redundancy and the energetic aspect of movement execution. Conversely, interarticular coordination and movement kinetics can reflect patients' motor strategies. This study investigates motor strategies of paretic and non-paretic upper limb after brain injury to highlight motor deficits or compensation strategies. METHODS: 26 brain-injured hemiplegic patients and 24 healthy controls performed active elbow extensions in the horizontal plane, with both upper limbs for patients and, with the dominant upper limb for controls. Elbow and shoulder kinematics, interarticular coordination, net joint kinetics were quantified. FINDINGS: Results show alterations in kinematics, and a strong correlation between elbow and shoulder angles, as well as time to reach elbow and shoulder peak angular velocity in both upper limbs of patients. Net joint kinetics were lower for paretic limb and highlighted a fragmented motor strategy with increased number of transitions between concentric and eccentric phases. INTERPRETATION: In complement to kinematic results, our kinetic results confirmed patients' difficulties to manage both spatially and temporally the joint degrees of freedom redundancy but revealed a fragmented compensatory motor strategy allowing patients upper limb extension despite quality alteration and decrease in energy efficiency. Motor rehabilitation should improve the management of this fragmentation strategy to improve the performance and the efficiency of active movement after brain injury.

The arthroscopic double-button Latarjet does not modify the static posterior translation of the humeral head.

INTRODUCTION: The Latarjet procedure treats anterior instability of the shoulder and is based on a triple anterior lock, where the conjoint tendon straps the lower third of the subscapularis muscle. Excessive posterior translation of the humeral head is a known risk factor for shoulder osteoarthritis. No in vivo study has investigated the effect of the bone block on the posterior static translation of the humeral epiphysis. The purpose of this study was to evaluate the effect of the bone block on the static posterior translation of the humeral head. The hypothesis was that this procedure increased this translation. MATERIALS AND METHODS: This retrospective study included patients treated arthroscopically for anterior shoulder instability by a double-button Latarjet. An independent examiner analyzed the CT scans preoperatively, at 15 days, and at least 6 months postoperatively according to a standardized protocol. The analysis focused on the position of the bone block in the axial and coronal planes relative to the glenoid. The posterior translation was automatically calculated using the Blueprint© planning software. RESULTS: Thirty-five patients were included with a mean age of 25 years (16-43), according to a 4M/1F sex ratio. The graft was perfectly flush to the subchondral bone in 63% (n=22) of cases and subequatorial in 91% (n=32). Preoperative posterior humeral translation was 52%. The mean immediate postoperative posterior humeral translation was 56%, and 57% at more than 6 months. The change in mean posterior humeral translation between preoperative/6 months was +0.94% [-20%; +12%] (p=0.29) and immediate postoperative/6 months +0.34% [-18%; +15%] (p=0.84). Gender, hypermobility and the axial position of the bone block did not influence the change in posterior humeral translation. The equatorial position of the bone block appeared to increase posterior humeral translation by +10%±5.2% [-0.427; 20.823] (p=0.07). CONCLUSION: This work refutes our initial hypothesis. The change in static posterior humeral translation after arthroscopic Latarjet bone block remains stable at more than 6 months of follow-up. This procedure does not alter the anatomical position of the humeral head in relation to the glenoid. On the other hand, a more cranial positioning of the bone block could have an influence. LEVEL OF EVIDENCE: IV.

Biomechanical modeling for the estimation of muscle forces: toward a common language in biomechanics, medical engineering, and neurosciences.

Different research fields, such as biomechanics, medical engineering or neurosciences take part in the development of biomechanical models allowing for the estimation of individual muscle forces involved in motor action. The heterogeneity of the terminology used to describe these models according to the research field is a source of confusion and can hamper collaboration between the different fields. This paper proposes a common language based on lexical disambiguation and a synthesis of the terms used in the literature in order to facilitate the understanding of the different elements of biomechanical modeling for force estimation, without questioning the relevance of the terms used in each field or the different model components or their interest. We suggest that the description should start with an indication of whether the muscle force estimation problem is solved following the physiological movement control (from the nervous drive to the muscle force production) or in the opposite direction. Next, the suitability of the model for force production estimation at a given time or for monitoring over time should be specified. Authors should pay particular attention to the method description used to find solutions, specifying whether this is done during or after data collection, with possible method adaptations during processing. Finally, the presence of additional data must be specified by indicating whether they are used to drive, assist, or calibrate the model. Describing and classifying models in this way will facilitate the use and application in all fields where the estimation of muscle forces is of real, direct, and concrete interest.

Sensitization Pathways in NIR-Emitting Yb(III) Complexes Bearing 0, +1, +2, or +3 Charges.

Yb(III) complexes of macrocyclic ligands based on 1,4,7,10-tetraazacyclododecane were synthesized. The ligands carried a carbostyril chromophore for Yb(III) sensitization, and carboxylate or carbamide donors for metal binding, forming complexes of 0, +1, +2, or +3 overall charge. The coordination geometry was little affected by the replacement of carboxylates with amides, as shown by paramagnetic 1H NMR spectroscopy. The Yb(III)/Yb(II) reduction potentials were dependent on the nature of the metal binding site, and the more positively charged complexes were easier to reduce. Carbostyril excitation resulted in Yb(III) luminescence in every complex. The residual carbostyril fluorescence quantum yields were smaller in complexes containing more reducible Yb(III) centers decreasing from 5.9% for uncharged complexes to 3.1-4.4% in +3 charged species, suggesting photoinduced electron transfer (PeT) from the antenna to the Yb(III). The relative Yb(III) luminescence quantum yields were identical within the experimental error, except for the +3 charged complex with fully methylated coordinating amides, which was the most intense Yb(III) emitter of the series in water. Quenching of the Yb(III) excited state by NH vibrations proved to limit Yb(III) emission. No clear improvement of the Yb(III) sensitization efficiency was shown upon faster PeT. This result can be explained by the concomitant sensitization of Yb(III) by phonon-assisted energy transfer (PAEnT) from the antenna triplet excited state, which was completely quenched in all of the Yb complexes. Depopulation of the triplet by PeT quenching of the donor singlet excited state would be compensated by the sensitizing nature of the PeT pathway, thus resulting in a constant overall sensitization efficiency across the series.

Why the Ala-His-His Peptide Is an Appropriate Scaffold to Remove and Redox Silence Copper Ions from the Alzheimer's-Related Aß Peptide.

The progressive, neurodegenerative Alzheimer's disease (AD) is the most widespread dementia. Due to the ageing of the population and the current lack of molecules able to prevent or stop the disease, AD will be even more impactful for society in the future. AD is a multifactorial disease, and, among other factors, metal ions have been regarded as potential therapeutic targets. This is the case for the redox-competent Cu ions involved in the production of reactive oxygen species (ROS) when bound to the Alzheimer-related Aß peptide, a process that contributes to the overall oxidative stress and inflammation observed in AD. Here, we made use of peptide ligands to stop the Cu(Aß)-induced ROS production and we showed why the AHH sequence is fully appropriate, while the two parents, AH and AAH, are not. The AHH peptide keeps its beneficial ability against Cu(Aß)-induced ROS, even in the presence of ZnII-competing ions and other biologically relevant ions. The detailed kinetic mechanism by which AHH could exert its action against Cu(Aß)-induced ROS is also proposed.

Improved emission of Yb(III) ions in triazacyclononane-based macrocyclic ligands compared to cyclen-based ones.

Yb(III) complexes based on ligands with a 1,4,7-triazacyclononane (tacn) macrocyclic core were synthesised. The complexes carry a 4-methoxymethyl-substituted carbostyril chromophore that serves as a light-harvesting antenna. The ligands supply 5 nitrogen and 3 oxygen donors via 1 methylenecarboxamide and 2 picolinate donors, creating +1 charged complexes with an octadentate binding environment. The electronic properties of the picolinates are modulated by varying the substitution at the 4 position with OMe, H, Cl, or CF3. Cyclic voltammetry indicated that the tacn-based Yb(III) complexes were easier to reduce than the analogous cyclen complexes. The first reductive event is likely picolinate-centred, followed by the formation of further reduced species. Antenna excitation yielded Yb(III) luminescence in the near-infrared (NIR) region in all cases. The antenna photophysical properties were consistent with intraligand photoinduced electron transfer from the excited carbostyril to the picolinate groups. The relative quantum yields of Yb(III) luminescence were determined. The lowest value was obtained for the complex with the most efficient antenna-to-picolinate photoinduced electron transfer. Despite intraligand electron transfer quenching of the antenna, the tacn-based Yb complexes were more emissive than their cyclen analogues, highlighting the influence of the ligand structure on the luminescence properties of NIR emissive lanthanide(III) ions.

Evaluation of the compounds commonly known as superoxide dismutase and catalase mimics in cellular models.

Oxidative stress that results from an imbalance between the concentrations of reactive species (RS) and antioxidant defenses is associated with many pathologies. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase are among the key enzymes that maintain the low nanomolar physiological concentrations of superoxide and hydrogen peroxide. The increase in the levels of these species and their progeny could have deleterious effects. In this context, chemists have developed SOD and CAT mimics to supplement them when cells are overwhelmed with oxidative stress. However, the beneficial activity of such molecules in cells depends not only on their intrinsic catalytic activities but also on their stability in biological context, their cell penetration and their cellular localization. We have employed cellular assays to characterize several compounds that possess SOD and CAT activities and have been frequently used in cellular and animal models. We used cellular assays that address SOD and CAT activities of the compounds. Finally, we determined the effect of compounds on the suppression of the inflammation in HT29-MD2 cells challenged by lipopolysaccharide. When the assay requires penetration inside cells, the SOD mimics Mn(III) meso-tetrakis(N-(2'-n-butoxyethyl)pyridinium-2-yl)porphyrin (MnTnBuOE-2-PyP5+) and Mn(II) dichloro[(4aR,13aR,17aR,21aR)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-eicosahydro-11,7-nitrilo-7Hdibenzo[b,h] [1,4, 7,10] tetraazacycloheptadecine-κN5,κN13,κN18,κN21,κN22] (Imisopasem manganese, M40403, CG4419) were found efficacious at 10 µM, while Mn(II) chloro N-(phenolato)-N,N'-bis[2-(N-methyl-imidazolyl)methyl]-ethane-1,2-diamine (Mn1) requires an incubation at 100 µM. This study thus demonstrates that MnTnBuOE-2-PyP5+, M40403 and Mn1 were efficacious in suppressing inflammatory response in HT29-MD2 cells and such action appears to be related to their ability to enter the cells and modulate reactive oxygen species (ROS) levels.

Lanthanide(III) Complexes of Cyclen Triacetates and Triamides Bearing Tertiary Amide-Linked Antennae.

The coordination compounds of the trivalent lanthanide ions (Ln(III)) have unique photophysical properties. Ln(III) excitation is usually performed through a light-harvesting antenna. To enable Ln(III)-based emitters to reach their full potential, an understanding of how complex structure affects sensitization and quenching processes is necessary. Here, the role of the linker between the antenna and the metal binding fragment was studied. Four macrocyclic ligands carrying coumarin 2 or 4-methoxymethylcarbostyril sensitizing antennae linked to an octadentate macrocyclic ligand binding site were synthesized. Complexation with Ln(III) (Ln = La, Sm, Eu, Gd, Tb, Yb and Lu) yielded species with overall -1, 0, or +2 and +3-charge. Paramagnetic 1H NMR spectroscopy indicated subtle differences between the coumarin- and carbostyril-carrying Eu(III) and Yb(III) complexes. Cyclic voltammetry showed that the effect of the linker on the Eu(III)/Eu(II) apparent reduction potential was dependent on the electronic properties of the N-substituent. The Eu(III), Tb(III) and Sm(III) complexes were all luminescent. Coumarin-sensitized complexes were poorly emissive; photoinduced electron transfer was not a major quenching pathway in these species. These results show that seemingly similar emitters can undergo very different photophysical processes, and highlight the crucial role the linker can play.

Coordination Environment-Controlled Photoinduced Electron Transfer Quenching in Luminescent Europium Complexes.

The quenching of sensitized Eu(III) luminescence by photoinduced electron transfer from the excited light-harvesting antenna to Eu(III) was investigated. A series of complexes incorporating different metal binding sites and thus having varying Eu(III)/Eu(II) reduction potentials were prepared. The complexes were fully characterized using a combination of single-crystal X-ray crystallography and paramagnetic 1H NMR spectroscopy, the results of which support the structural similarity of the complexes. The redox and photophysical behavior of the Eu(III) center and the light-harvesting antenna were studied using cyclic voltammetry and steady-state and time-resolved emission spectroscopy on the nanosecond and millisecond time scales. The contribution of photoinduced electron transfer to the overall reduction of the Eu(III) luminescence quantum yield was found to be comparable and, in many cases, larger than the quenching caused by well-established processes such as coupling to X-H oscillators. These results suggest that the elimination or mitigation of photoinduced electron transfer could substantially improve the emissive properties of the widely used Eu(III)-based emitters.

Intracellular location matters: rationalization of the anti-inflammatory activity of a manganese(ii) superoxide dismutase mimic complex.

A conjugate of a Mn-based superoxide dismutase mimic with a Re-based multimodal probe 1[combining low line] was studied in a cellular model of oxidative stress. Its speciation was investigated using Re and Mn X-fluorescence. Interestingly, 1[combining low line] shows a distribution different from its unconjugated analogue but a similar concentration in mitochondria and a similar bioactivity.

Anti-inflammatory activity of superoxide dismutase mimics functionalized with cell-penetrating peptides.

A superoxide dismutase mimic (Mn1) was functionalized with three positively charged-peptides: RRRRRRRRR (Mn1-R9), RRWWWRRWRR (Mn1-RW9) or Fx-r-Fx-K (Mn1-MPP). Characterization of the physico-chemical properties of the complexes show that they share similar binding affinity for Mn2+, apparent reduction potential and intrinsic superoxide dismutase activity. However, their accumulation in cells is different (Mn1-R9 < Mn1-MPP < Mn1-RW9 < Mn1), as well as their subcellular distribution. In addition, the three functionalized-complexes display a better anti-inflammatory activity than Mn1 when assayed at 10 µM. This improvement is due to a combination of an anti-inflammatory effect of the peptidyl moiety itself, and of the SOD mimic for Mn1-RW9 and Mn1-MPP. In contrast, the enhanced anti-inflammatory activity of Mn1-R9 is solely due to the SOD mimic.

Rational De Novo Design of a Cu Metalloenzyme for Superoxide Dismutation.

Superoxide dismutases (SODs) are highly efficient enzymes for superoxide dismutation and the first line of defense against oxidative stress. These metalloproteins contain a redox-active metal ion in their active site (Mn, Cu, Fe, Ni) with a tightly controlled reduction potential found in a close range around the optimal value of 0.36 V versus the normal hydrogen electrode (NHE). Rationally designed proteins with well-defined three-dimensional structures offer new opportunities for obtaining functional SOD mimics. Here, we explore four different copper-binding scaffolds: H3 (His3 ), H4 (His4 ), H2 DH (His3 Asp with two His and one Asp in the same plane) and H3 D (His3 Asp with three His in the same plane) by using the scaffold of the de novo protein GRα3 D. EPR and XAS analysis of the resulting copper complexes demonstrates that they are good CuII -bound structural mimics of Cu-only SODs. Furthermore, all the complexes exhibit SOD activity, though three orders of magnitude slower than the native enzyme, making them the first de novo copper SOD mimics.

Clarifying the Copper Coordination Environment in a de Novo Designed Red Copper Protein.

Cupredoxins are copper-dependent electron-transfer proteins that can be categorized as blue, purple, green, and red depending on the spectroscopic properties of the Cu(II) bound forms. Interestingly, despite significantly different first coordination spheres and nuclearity, all cupredoxins share a common Greek Key ß-sheet fold. We have previously reported the design of a red copper protein within a completely distinct three-helical bundle protein, α3DChC2. (1) While this design demonstrated that a ß-barrel fold was not requisite to recapitulate the properties of a native cupredoxin center, the parent peptide α3D was not sufficiently stable to allow further study through additional mutations. Here we present the design of an elongated protein GRANDα3D (GRα3D) with Δ Gu = -11.4 kcal/mol compared to the original design's -5.1 kcal/mol. Diffraction quality crystals were grown of GRα3D (a first for an α3D peptide) and solved to a resolution of 1.34 Å. Examination of this structure suggested that Glu41 might interact with the Cu in our previously reported red copper protein. The previous bis(histidine)(cysteine) site (GRα3DChC2) was designed into this new scaffold and a series of variant constructs were made to explore this hypothesis. Mutation studies around Glu41 not only prove the proposed interaction, but also enabled tuning of the constructs' hyperfine coupling constant from 160 to 127 × 10-4 cm-1. X-ray absorption spectroscopy analysis is consistent with these hyperfine coupling differences being the result of variant 4p mixing related to coordination geometry changes. These studies not only prove that an Glu41-Cu interaction leads to the α3DChC2 construct's red copper protein like spectral properties, but also exemplify the exact control one can have in a de novo construct to tune the properties of an electron-transfer Cu site.

Lanthanide-based tools for the investigation of cellular environments.

Biological probes constructed from lanthanides can provide a variety of readout signals, such as the luminescence of Eu(iii), Tb(iii), Yb(iii), Sm(iii) and Dy(iii), and the proton relaxation enhancement of Gd(iii) and Eu(ii). For numerous applications the intracellular delivery of the lanthanide probe is essential. Here, we review the methods for the intracellular delivery of non-targeted complexes (i.e. where the overall complex structure enhances cellular uptake), as well as complexes attached to a targeting unit (i.e. to a peptide or a small molecule) that facilitates delivery. The cellular applications of lanthanide-based supramolecules (dendrimers, metal organic frameworks) are covered briefly. Throughout, we emphasize the techniques that can confirm the intracellular localization of the lanthanides and those that enable the determination of the fate of the probes once inside the cell. Finally, we highlight methods that have not yet been applied in the context of lanthanide-based probes, but have been successful in the intracellular delivery of other metal-based probes.

Effect of the phase of force production on corticomuscular coherence with agonist and antagonist muscles.

During isometric contractions, the net joint torque stability is modulated with the force production phases, i.e., increasing (IFP), holding (HFP), and decreasing force (DFP) phases. It was hypothesized that this modulation results from an altered cortical control of agonist and antagonist muscle activations. Eleven healthy participants performed 50 submaximal isometric ankle plantar flexion contractions. The force production phase effect (IFP, HFP and DFP) was assessed on the net joint torque stability, agonist and antagonist muscles activations, cortical activation, and corticomuscular coherence (CMC) with agonist and antagonist muscles. In comparison to HFP, the net joint torque stability, the agonist muscles activation and the CMC with agonist muscles were lower during IFP and even more during DFP. Antagonist muscle activations, cortical activations and CMC with antagonist muscles were higher during HFP than during IFP only. Increased CMC with agonist and antagonist muscles appeared to enhance the fine motor control. At a cortical level, agonist and antagonist muscle activations seemed to be controlled independently according to their muscle function and the phase of force production. Results revealed that CMC was an adequate measure to investigate the cortical regulation of agonist and antagonist muscle activations. This may have potential applications for patients with altered muscle activations.

Multi-target-directed phenol-triazole ligands as therapeutic agents for Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial disease that is characterized by the formation of intracellular neurofibrillary tangles and extracellular amyloid-ß (Aß) plaque deposits. Increased oxidative stress, metal ion dysregulation, and the formation of toxic Aß peptide oligomers are all considered to contribute to the etiology of AD. In this work we have developed a series of ligands that are multi-target-directed in order to address several disease properties. 2-(1-(3-Hydroxypropyl)-1H-1,2,3-triazol-4-yl)phenol (POH), 2-(1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)phenol (PMorph), and 2-(1-(2-thiomorpholinoethyl)-1H-1,2,3-triazol-4-yl)phenol (PTMorph) have been synthesized and screened for their antioxidant capacity, Cu-binding affinity, interaction with the Aß peptide and modulation of Aß peptide aggregation, and the ability to limit Aß1-42-induced neurotoxicity in human neuronal culture. The synthetic protocol and structural variance incorporated via click chemistry, highlights the influence of R-group modification on ligand-Aß interactions and neuroprotective effects. Overall, this study demonstrates that the phenol-triazole ligand scaffold can target multiple factors associated with AD, thus warranting further therapeutic development.

A Cell-Penetrant Manganese Superoxide Dismutase (MnSOD) Mimic Is Able To Complement MnSOD and Exerts an Antiinflammatory Effect on Cellular and Animal Models of Inflammatory Bowel Diseases.

Inorganic complexes are increasingly used for biological and medicinal applications, and the question of the cell penetration and distribution of metallodrugs is key to understanding their biological activity. Oxidative stress is known to be involved in inflammation and in inflammatory bowel diseases for which antioxidative defenses are weakened. We report here the study of the manganese complex Mn1 mimicking superoxide dismutase (SOD), a protein involved in cell protection against oxidative stress, using an approach in inorganic cellular chemistry combining the investigation of Mn1 intracellular speciation using mass spectrometry and of its quantification and distribution using electron paramagnetic resonance and spatially resolved X-ray fluorescence with evaluation of its biological activity. More precisely, we have looked for and found the MS signature of Mn1 in cell lysates and quantified the overall manganese content. Intestinal epithelial cells activated by bacterial lipopolysaccharide were taken as a cellular model of oxidative stress and inflammation. DNBS-induced colitis in mice was used to investigate Mn1 activity in vivo. Mn1 exerts an intracellular antiinflammatory activity, remains at least partially coordinated, with diffuse distribution over the whole cell, and functionally complements mitochondrial MnSOD.

Bioinspired superoxide-dismutase mimics: The effects of functionalization with cationic polyarginine peptides.

Continuing a bio-mimetic approach, we have prepared peptide conjugates of a superoxide dismutase (SOD) mimic [MnL](+) (where HL=N-(2-hydroxybenzyl)-N,N'-bis[2-(N-methylimidazolyl)methyl]ethane-1,2-diamine), namely [MnL'-Arg(n-1)](n+) (where n=2, 4, 7 and 10) and [MnL'-Gly1](+). [MnL'-Arg(n-1)](n+) contained cationic residue(s) that emulate the electrostatic channel of the enzyme. Physicochemical methods showed that functionalization at the secondary amine of HL did not impair coordination to Mn(II) with association constants (Kassoc) between 1.6 and 3.3×10(6)M(-1). The Mn(III)/Mn(II) redox potential of the conjugates was between 0.27 and 0.30V vs SCE, slightly higher than [MnL](+) under the same conditions, but remain at a value that facilitates O2(-) dismutation. The catalytic rate constant (kcat) of the dismutation for the series was studied using a direct stopped-flow method, which showed that for compounds with the same overall charge, the alkylation of the secondary amine of [MnL](+) (kcat=5.0±0.1×10(6)M(-1)s(-1)) led to a lower value (i.e. for [MnL'Gly](+), kcat=4.2±0.1×10(6)M(-1)s(-1)). However, under the same conditions, kcat values between 5.0±0.4×10(6)M(-1)s(-1) and 6.6±0.1×10(6)M(-1)s(-1) were determined for [MnL'-Arg(n-1)](n+) conjugates, indicating that the cationic residue(s) compensated for the loss in activity. Analysis of the effect of ionic strength on the kcat strongly suggested that not all the charges were involved, but only the closest ones electrostatically influenced the SOD active metal centre.

Comparison of CR36, a new heparan mimetic, and pentosan polysulfate in the treatment of prion diseases.

Sulfated polyanions, including pentosan polysulfate (PPS) and heparan mimetics, number among the most effective drugs that have been used in experimental models of prion disease and are presumed to act in competition with endogenous heparan sulfate proteoglycans as co-receptors for prion protein (PrP) on the cell surface. PPS has been shown to prolong the survival of animals after intracerebral perfusion and is in limited use for the experimental treatment of human transmissible spongiform encephalopathies (TSEs). Here, PPS is compared with CR36, a new heparan mimetic. Ex vivo, CR36 was more efficient than PPS in reducing PrPres in scrapie-infected cell cultures and showed long-lasting activity. In vivo, CR36 showed none of the acute toxicity observed with PPS and reduced PrPres accumulation in spleens, but had only a marginal effect on the survival time of mice infected with bovine spongiform encephalopathy. In contrast, mice treated with PPS that survived the initial toxic mortality had no detectable PrPres in the spleens and lived 185 days longer than controls (+55%). These results show, once again, that anti-TSE drugs cannot be encouraged for human therapeutic trials solely on the basis of in vitro or ex vivo observations, but must first be subjected to in vivo animal studies.

Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome.

BACKGROUND: Recent studies have suggested that ex vivo expansion of autologous hematopoietic cells could be a therapy of choice for the treatment of bone marrow failure. We investigated the potential of a combined infusion of autologous ex vivo expanded hematopoietic cells with mesenchymal (MSCs) for the treatment of multi-organ failure syndrome following irradiation in a non-human primate model. METHODS: Hematopoietic cells and MSCs were expanded from bone marrow aspirates. MSCs were transduced with the gene encoding for the green fluorescent protein (e-GFP), in order to track them following infusion. Twelve animals were studied. Nine animals received total-body irradiation at 8 Gy from a neutron/gamma source thus resulting in heterogeneous exposure; three animals were sham-irradiated. The animals were treated with expanded hematopoietic stem cells and MSCs, expanded hematopoietic stem cells alone, or MSCs alone. Unmanipulated bone marrow cell transplants were used as controls. RESULTS: Depending on the neutron/gamma ratio, an acute radiation sickness of varying severity but of similar nature resulted. GFP-labeled cells were found in the injured muscle, skin, bone marrow and gut of the treated animals via PCR up to 82 days post-infusion. CONCLUSIONS: This is the first evidence of expanded MSCs homing in numerous tissues following a severe multi-organ injury in primates. Localization of the transduced MSCs correlated to the severity and geometry of irradiation. A repair process was observed in various tissues. The plasticity potential of the MSCs and their contribution to the repair process in vivo remains to be studied.