Intravenous transplantation of bone marrow-derived mesenchymal stromal cells in patients with multiple sclerosis, a phase I/IIa, double blind, randomized controlled study.

Multiple sclerosis (MS) is a progressive, demyelinating neurodegenerative disease of the central nervous system. MS is immune-mediated and leads to disability especially in young adults. Even though 18 MS therapy drugs were approved, they slightly inhibit disease progression and do not induce regeneration and repair in the nervous system. Mesenchymal stromal cells (MSCs) have emerged as a new therapeutic modality in regenerative medicine and tissue engineering due to their immunomodulation and bio regenerative properties. We have designed a randomized, controlled clinical trial to assess safety and possible efficacy of MSC application in MS patients. Twenty-one MS patients were enrolled. Patients were allocated in two distinct groups: treatment group, which received systemic transplantation of autologous bone marrow-derived MSCs, and control group, which received placebo at the first injections. Patients in control group received MSCs at the second injection while the treatment group received placebo. All the patients were followed for 18 months. Follow-ups included regular visits, laboratory evaluation, and imaging analysis. Control patients received MSCs six month after treatment group. No severe immediate or late adverse events were observed in both groups after interventions. We did not find any significant differences in the rate of relapses, Expanded Disability Status Scale (EDSS) score, cognitive condition, Magnetic Resonance Imaging (MRI) findings, or any biomarkers of cerebrospinal fluid between the two groups and in each group before and after cell infusion. Transplantation of autologous bone marrow-derived mesenchymal stromal cells is safe and feasible. The efficacy of transplantation of these cells should be evaluated through designing randomized clinical trials with larger sample sizes, different administration routes, other cell types (allogeneic adipose derived MSCs, allogeneic Wharton's jelly derived MSCs …), repeated injections, and longer follow-up periods.

Chronic ozone exposure impairs the mineral nutrition of date palm (Phoenix dactylifera) seedlings.

Chronic ozone (O3) exposure in the atmosphere preferentially disturbs metabolic processes in the roots rather than the shoot as a consequence of reduced photosynthesis and carbohydrate allocation from the leaves to the roots. The aim of the present study was to elucidate if mineral nutrition is also impaired by chronic O3 exposure. For this purpose, date palm (Phoenix dactylifera) plants were fumigated with ambient, 1.5 × ambient and 2 × ambient O3 in a free air controlled exposure (FACE) system for one growing season and concentrations of major nutrients were analyzed in leaves and roots. In addition, concentrations of C and N and their partitioning between different metabolic C and N pools were determined in both organs. The results showed that calcium (Ca), magnesium (Mg), iron (Fe), zinc (Zn), sodium (Na) and potassium (K) acquisition by roots was diminished by O3 exposure of the shoot. For Ca, Mg, Fe and Zn reduced uptake by the roots was combined with reduced allocation to the shoot, resulting in a decline of foliar concentrations; for Na and K, allocation to the shoot was maintained at the expense of the roots. Thus, elevated O3 impaired both mineral uptake by the roots and partitioning of minerals between roots and shoots, but in an element specific way. Thereby, elevated O3 affected roots and shoots differently already after one growing season. However, considerable changes in total C and N concentrations and their partitioning between different metabolic pools upon chronic O3 exposure were not observed in either leaves or roots, except for reduced foliar lignin concentrations at 2 × ambient O3. Significant differences in these parameters were shown between leaves and roots independent of O3 application. The physiological consequences of the effects of chronic O3 exposure on mineral acquisition and partitioning between leaves and roots are discussed.

Date palm responses to a chronic, realistic ozone exposure in a FACE experiment.

Date palms are highly economically important species in hot arid regions, which may suffer ozone (O3) pollution equivalently to heat and water stress. However, little is known about date palm sensitivity to O3. Therefore, to identify their resistance mechanisms against elevated O3, physiological parameters (leaf gas exchange, chlorophyll fluorescence and leaf pigments) and biomass growth responses to realistic O3 exposure were tested in an isoprene-emitting date palm (Phoenix dactylifera L. cv. Nabut Saif) by a Free-Air Controlled Exposure (FACE) facility with three levels of O3 (ambient [AA, 45 ppb as 24-h average], 1.5 x AA and 2 x AA). We found a reduction of photosynthesis only at 2 x AA although some foliar traits known as early indicators of O3 stress responded already at 1.5 x AA, such as increased dark respiration, reduced leaf pigment content, reduced maximum quantum yield of PSII, inactivation of the oxygen evolving complex of PSII and reduced performance index PITOT. As a result, O3 did not affect most of the growth parameters although significant declines of root biomass occurred only at 2 x AA. The major mechanism in date palm for reducing the severity of O3 impacts was a restriction of stomatal O3 uptake due to low stomatal conductance and O3-induced stomatal closure. In addition, an increased respiration in elevated O3 may indicate an enhanced capacity of catabolizing metabolites for detoxification and repair. Interestingly, date palm produced low amounts of monoterpenes, whose emission was stimulated in 2 x AA, although isoprene emission declined at both 1.5 and 2 x AA. Our results warrant more research on a biological significance of terpenoids in plant resistance against O3 stress.

Safety and Efficacy of Allogeneic Adipose Tissue Mesenchymal Stromal Cells in Amyotrophic Lateral Sclerosis Patients, Single-Center, Prospective, Open-Label, Single-Arm Clinical Trial, Long-Term Follow-up.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with very limited treatment options. Stem cells have been raised as a new treatment modality for these patients. We have designed a single-center, prospective, open-label, and single arm clinical trial to assess the safety, feasibility, and rather efficacy of administrating allogeneic adipose-derived mesenchymal stromal cells (Ad-MSCs) in ALS patients. We enrolled 17 patients with confirmed ALS diagnosis with ALS Functional Rating Scale-Revised (ALSFRS-R) ≥24 and predicted forced vital capacity (FVC) ≥40%. Allogeneic Ad-MSCs were transplanted intravenously for all patients. Follow-ups were done at 24 hours, 2, 4, 6, and 12 months after cell infusion by checking adverse events, laboratory tests, and clinically by ALSFRS-R and FVC. Patients were also followed five years later and ALSFRS-R score was recorded in the survived individuals. There was no report of severe adverse events related to cell infusion. Two patients experienced dyspnea and chest pain 36 and 65 days after cell infusion due to pulmonary emboli. The progressive decrease in ALSFRS-R and FVC levels was recorded and three patients died in the first year. During five years follow up, despite a notable decrease in functional scores, 5 patients survived. Intravenous (IV) infusion of allogeneic Ad-MSCs in ALS patients is safe and feasible. The survival rate of the patients is more than IV autologous MSCs (Registration number: IRCT20080728001031N26).

Physiological responses of date palm (Phoenix dactylifera) seedlings to seawater and flooding.

In their natural environment along coast lines, date palms are exposed to seawater inundation and, hence, combined stress by salinity and flooding. To elucidate the consequences of this combined stress on foliar gas exchange and metabolite abundances in leaves and roots, date palm seedlings were exposed to flooding with seawater and its major constituents under controlled conditions. Seawater flooding significantly reduced CO2 assimilation, transpiration and stomatal conductance, but did not affect isoprene emission. A similar effect was observed upon NaCl exposure. By contrast, flooding with distilled water or MgSO4 did not affect CO2 /H2 O gas exchange or stomatal conductance significantly, indicating that neither flooding itself, nor seawater sulfate, contributed greatly to stomatal closure. Seawater exposure increased Na and Cl contents in leaves and roots, but did not affect sulfate contents significantly. Metabolite analyses revealed reduced abundances of foliar compatible solutes, such as sugars and sugar alcohols, whereas nitrogen compounds accumulated in roots. Reduced transpiration upon seawater exposure may contribute to controlling the movement of toxic ions to leaves and, therefore, can be seen as a mechanism to cope with salinity. The present results indicate that date palm seedlings are tolerant towards seawater exposure to some extent, and highly tolerant to flooding.

Hyperspectral Reflectance of Light-Adapted Leaves Can Predict Both Dark- and Light-Adapted Chl Fluorescence Parameters, and the Effects of Chronic Ozone Exposure on Date Palm (Phoenix dactylifera).

High-throughput and large-scale measurements of chlorophyll a fluorescence (ChlF) are of great interest to investigate the photosynthetic performance of plants in the field. Here, we tested the capability to rapidly, precisely, and simultaneously estimate the number of pulse-amplitude-modulation ChlF parameters commonly calculated from both dark- and light-adapted leaves (an operation which usually takes tens of minutes) from the reflectance of hyperspectral data collected on light-adapted leaves of date palm seedlings chronically exposed in a FACE facility to three ozone (O3) concentrations (ambient air, AA; target 1.5 × AA O3, named as moderate O3, MO; target 2 × AA O3, named as elevated O3, EO) for 75 consecutive days. Leaf spectral measurements were paired with reference measurements of ChlF, and predictive spectral models were constructed using partial least squares regression. Most of the ChlF parameters were well predicted by spectroscopic models (average model goodness-of-fit for validation, R2: 0.53-0.82). Furthermore, comparing the full-range spectral profiles (i.e., 400-2400 nm), it was possible to distinguish with high accuracy (81% of success) plants exposed to the different O3 concentrations, especially those exposed to EO from those exposed to MO and AA. This was possible even in the absence of visible foliar injury and using a moderately O3-susceptible species like the date palm. The latter view is confirmed by the few variations of the ChlF parameters, that occurred only under EO. The results of the current study could be applied in several scientific fields, such as precision agriculture and plant phenotyping.

Foliar traits of sessile oak (Quercus petraea Liebl) seedlings are largely determined by site properties rather than seed origin.

Due to climate change, sessile oak (Quercus petraea) seedlings experience an increasing risk of drought during regeneration of forest stands by management practices. The present study was aimed at elucidating the potential of sessile oak seedlings originating from sites with different aridity and nitrogen (N) supply to acclimate to contrasting water availability. For this purpose, a free-air cross-exchange experiment was conducted between a dry and a humid forest stand with high and low soil N contents, respectively, during two consecutive years differing in aridity before harvest. Almost all structural and physiological foliar traits analyzed did not differ consistently between seed origins during both years, when cultivated at the same site. As an exception, the arid provenance upregulated foliar ascorbate contents under drought, whereas the humid provenance accumulated the phenolic antioxidants vescalagin and castalagin (VC) under favorable weather conditions and consumed VC upon drought. Apparently, differences in long-term aridity at the forest sites resulted in only few genetically fixed differences in foliar traits between the provenances. However, structural and physiological traits strongly responded to soil N contents and weather conditions before harvest. Foliar N contents and their partitioning were mostly determined by the differences in soil N availability at the sites, but still were modulated by weather conditions before harvest. In the first year, differences in aridity before harvest resulted in differences between most foliar traits. In the second year, when weather conditions at both sites were considerably similar and more arid compared to the first year, differences in foliar traits were almost negligible. This pattern was observed irrespective of seed origin. These results support the view that leaves of sessile oak seedlings generally possess a high plasticity to cope with extreme differences in aridity by immediate acclimation responses that are even better developed in plants of arid origin.

Corrigendum: Knock-Down of the Phosphoserine Phosphatase Gene Effects Rather N- Than S-Metabolism in Arabidopsis thaliana.

[This corrects the article DOI: 10.3389/fpls.2018.01830.].

Safety, Feasibility of Intravenous and Intrathecal Injection of Autologous Bone Marrow Derived Mesenchymal Stromal Cells in Patients with Amyotrophic Lateral Sclerosis: An Open Label Phase I Clinical Trial.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is the most severe disorder within the spectrum of motor neuron diseases (MND) that has no effective treatment and a progressively fatal outcome. We have conducted two clinical trials to assess the safety and feasibility of intravenous (IV) and intrathecal (IT) injections of bone marrow derived mesenchymal stromal cells (BM-MSCs) in patients with ALS. MATERIALS AND METHODS: This is an interventional/experimental study. We enrolled 14 patients that met the following inclusion criteria: definitive diagnosis of sporadic ALS, ALS Functional Rating Scale (ALS-FRS) ≥24, and ≥40% predicted forced vital capacity (FVC). All patients underwent bone marrow (BM) aspiration to obtain an adequate sample for cell isolation and culture. Patients in group 1 (n=6) received an IV and patients in group 2 (n=8) received an IT injection of the cell suspension. All patients in both groups were followed at 24 hours and 2, 4, 6, and 12 months after the injection with ALS-FRS, FVC, laboratory tests, check list of side effects and brain/spinal cord magnetic resonance imaging (MRI). In each group, one patient was lost to follow up one month after cell injection and one patient from IV group died due to severe respiratory insufficiency and infection. RESULTS: During the follow up there were no reports of adverse events in terms of clinical and laboratory assessments. In MRI, there was not any new abnormal finding. The ALS-FRS score and FVC percentage significantly reduced in all patients from both groups. CONCLUSION: This study has shown that IV and IT transplantation of BM-derived stromal cells is safe and feasible (Registration numbers: NCT01759797 and NCT01771640).

Atmospheric pCO2 impacts leaf structural and physiological traits in Quercus petraea seedlings.

MAIN CONCLUSION: Atmospheric p CO 2 impacts Quercus petraea biomass production and cell wall composition of the leaves in favor of cellulose at the expense of lignin, and enhances foliar non-structural carbohydrate levels and sucrose contents in a pCO 2 concentration-dependent manner. Sessile oak (Quercus petraea Liebl.) was grown for ca. half a year from seeds at ambient control (525 ppm), 750, 900, and 1000 ppm atmospheric pCO2 under controlled conditions. Increasing pCO2 enhanced biomass production, modified the cell wall composition of the leaves in favor of cellulose at the expense of lignin, and enhanced the foliar non-structural carbohydrate level, in particular the sucrose content; as well as total N content of leaves by increased levels of all major N fractions, i.e., soluble proteins, total amino acids, and structural N. The enhanced total amino acid level was largely due to 2-ketoglutarate and oxalo acetate-derived compounds. Increasing pCO2 alleviated oxidative stress in the leaves as indicated by reduced H2O2 contents. High in vitro glutathione reductase activity at reduced H2O2 contents suggests enhanced ROS scavenging, but increased lipid peroxidation may also have contributed, as indicated by a negative correlation between malone dialdehyde and H2O2 contents. Almost all these effects were at least partially reversed, when pCO2 exceeded 750 or 900 ppm. Apparently, the interaction of atmospheric pCO2 with leaf structural and physiological traits of Q. petraea seedlings is characterized by a dynamic response depending on the pCO2 level.

Stem cell therapy in Alzheimer's disease: possible benefits and limiting drawbacks.

Alzheimer's disease (AD) is the sixth leading cause of death globally and the main reason for dementia in elderly people. AD is a long-term and progressive neurodegenerative disorder that steadily worsens memory and communicating skills eventually leads to a disabled person of performing simple daily tasks. Unfortunately, numerous clinical trials exploring new therapeutic drugs have encountered disappointing outcomes in terms of improved cognitive performance since they are not capable of halting or stimulating the regeneration of already-damaged neural cells, and merely provide symptomatic relief. Therefore, a deeper understanding of the mechanism of action of stem cell may contribute to the development of novel and effective therapies. The revolutionary discovery of stem cells has cast a new hope for the development of disease-modifying treatments for AD, in terms of their potency in the replenishment of lost cells via differentiating towards specific lineages, stimulating in situ neurogenesis, and delivering the therapeutic agents to the brain. Herein, firstly, we explore the pathophysiology of AD. Next, we summarize the most recent preclinical stem cell reports designed for AD treatment, their benefits and outcomes according to cell type. We briefly review relevant clinical trials and their potential clinical applications in order to find a unique solution to effectively relieve the patients' pain.

The Photorespiratory BOU Gene Mutation Alters Sulfur Assimilation and Its Crosstalk With Carbon and Nitrogen Metabolism in Arabidopsis thaliana.

This study was aimed at elucidating the significance of photorespiratory serine (Ser) production for cysteine (Cys) biosynthesis. For this purpose, sulfur (S) metabolism and its crosstalk with nitrogen (N) and carbon (C) metabolism were analyzed in wildtype Arabidopsis and its photorespiratory bou-2 mutant with impaired glycine decarboxylase (GDC) activity. Foliar glycine and Ser contents were enhanced in the mutant at day and night. The high Ser levels in the mutant cannot be explained by transcript abundances of genes of the photorespiratory pathway or two alternative pathways of Ser biosynthesis. Despite enhanced foliar Ser, reduced GDC activity mediated a decline in sulfur flux into major sulfur pools in the mutant, as a result of deregulation of genes of sulfur reduction and assimilation. Still, foliar Cys and glutathione contents in the mutant were enhanced. The use of Cys for methionine and glucosinolates synthesis was reduced in the mutant. Reduced GDC activity in the mutant downregulated Calvin Cycle and nitrogen assimilation genes, upregulated key enzymes of glycolysis and the tricarboxylic acid (TCA) pathway and modified accumulation of sugars and TCA intermediates. Thus, photorespiratory Ser production can be replaced by other metabolic Ser sources, but this replacement deregulates the cross-talk between S, N, and C metabolism.

COMPARE CPM-RMI Trial: Intramyocardial Transplantation of Autologous Bone Marrow-Derived CD133+ Cells and MNCs during CABG in Patients with Recent MI: A Phase II/III, Multicenter, Placebo-Controlled, Randomized, Double-Blind Clinical Trial.

This article published in Cell J (Yakhteh), Vol 20, No 2, Jul-Sep 2018, on pages 267-277, four affiliations (1, 4, 5, and 10) were changed based on authors request.

COMPARE CPM-RMI Trial: Intramyocardial Transplantation of Autologous Bone Marrow-Derived CD133+ Cells and MNCs during CABG in Patients with Recent MI: A Phase II/III, Multicenter, Placebo-Controlled, Randomized, Double-Blind Clinical Trial.

OBJECTIVES: The regenerative potential of bone marrow-derived mononuclear cells (MNCs) and CD133+ stem cells in the heart varies in terms of their pro-angiogenic effects. This phase II/III, multicenter and double-blind trial is designed to compare the functional effects of intramyocardial autologous transplantation of both cell types and placebo in patients with recent myocardial infarction (RMI) post-coronary artery bypass graft. MATERIALS AND METHODS: This was a phase II/III, randomized, double-blind, placebo-controlled trial COMPARE CPM-RMI (CD133, Placebo, MNCs - recent myocardial infarction) conducted in accordance with the Declaration of Helsinki that assessed the safety and efficacy of CD133 and MNCs compared to placebo in patients with RMI. We randomly assigned 77 eligible RMI patients selected from 5 hospitals to receive CD133+ cells, MNC, or a placebo. Patients underwent gated single photon emission computed tomography assessments at 6 and 18 months post-intramyocardial transplantation. We tested the normally distributed efficacy outcomes with a mixed analysis of variance model that used the entire data set of baseline and between-group comparisons as well as within subject (time) and group×time interaction terms. RESULTS: There were no related serious adverse events reported. The intramyocardial transplantation of both cell types increased left ventricular ejection fraction by 9% [95% confidence intervals (CI): 2.14% to 15.78%, P=0.01] and improved decreased systolic wall thickening by -3.7 (95% CI: -7.07 to -0.42, P=0.03). The CD133 group showed significantly decreased non-viable segments by 75% (P=0.001) compared to the placebo and 60% (P=0.01) compared to the MNC group. We observed this improvement at both the 6- and 18-month time points. CONCLUSIONS: Intramyocardial injections of CD133+ cells or MNCs appeared to be safe and efficient with superiority of CD133+ cells for patients with RMI. Although the sample size precluded a definitive statement about clinical outcomes, these results have provided the basis for larger studies to confirm definitive evidence about the efficacy of these cell types (Registration Number: NCT01167751).

Knock-Down of the Phosphoserine Phosphatase Gene Effects Rather N- Than S-Metabolism in Arabidopsis thaliana.

The aim of present study was to elucidate the significance of the phosphorylated pathway of Ser production for Cys biosynthesis in leaves at day and night and upon cadmium (Cd) exposure. For this purpose, Arabidopsis wildtype plants as control and its psp mutant knocked-down in phosphoserine phosphatase (PSP) were used to test if (i) photorespiratory Ser is the dominant precursor of Cys synthesis in autotrophic tissue in the light, (ii) the phosphorylated pathway of Ser production can take over Ser biosynthesis in leaves at night, and (iii) Cd exposure stimulates Cys and glutathione (GSH) biosynthesis and effects the crosstalk of S and N metabolism, irrespective of the Ser source. Glycine (Gly) and Ser contents were not affected by reduction of the psp transcript level confirming that the photorespiratory pathway is the main route of Ser synthesis. The reduction of the PSP transcript level in the mutant did not affect day/night regulation of sulfur fluxes while day/night fluctuation of sulfur metabolite amounts were no longer observed, presumably due to slower turnover of sulfur metabolites in the mutant. Enhanced contents of non-protein thiols in both genotypes and of GSH only in the psp mutant were observed upon Cd treatment. Mutation of the phosphorylated pathway of Ser biosynthesis caused an accumulation of alanine, aspartate, lysine and a decrease of branched-chain amino acids. Knock-down of the PSP gene induced additional defense mechanisms against Cd toxicity that differ from those of WT plants.

Detecting early signs of heat and drought stress in Phoenix dactylifera (date palm).

Plants adapt to the environment by either long-term genome evolution or by acclimatization processes where the cellular processes and metabolism of the plant are adjusted within the existing potential in the genome. Here we studied the adaptation strategies in date palm, Phoenix dactylifera, under mild heat, drought and combined heat and drought by transcriptomic and metabolomic profiling. In transcriptomics data, combined heat and drought resembled heat response, whereas in metabolomics data it was more similar to drought. In both conditions, soluble carbohydrates, such as fucose, and glucose derivatives, were increased, suggesting a switch to carbohydrate metabolism and cell wall biogenesis. This result is consistent with the evidence from transcriptomics and cis-motif analysis. In addition, transcriptomics data showed transcriptional activation of genes related to reactive oxygen species in all three conditions (drought, heat, and combined heat and drought), suggesting increased activity of enzymatic antioxidant systems in cytosol, chloroplast and peroxisome. Finally, the genes that were differentially expressed in heat and combined heat and drought stresses were significantly enriched for circadian and diurnal rhythm motifs, suggesting new stress avoidance strategies.

Intravitreal Injection of Bone Marrow Mesenchymal Stem Cells in Patients with Advanced Retinitis Pigmentosa; a Safety Study.

PURPOSE: To examine the safety of a single intravitreal injection of autologous bone Marrow Mesenchymal stem cells (MSCs) in patients with advanced retinitis pigmentosa (RP). METHODS: A prospective, phase I, nonrandomized, open-label study was conducted on 3 eyes of 3 volunteers with advanced RP. Visual acuity, slit-lamp examination, fundus examination, optical coherence tomography, fundus auto-fluorescence, fluorescein angiography and multifocal electroretinography were performed before and after an intravitreal injection of approximately one-million MSCs. The patients were followed for one year. Further evaluation of MSCs was performed by injection of these cells into the mouse vitreous cavity. RESULTS: No, adverse events were observed in eyes of 2 out of 3 patients after transplantation of MSCs. These patients reported improvements in perception of the light after two weeks, which lasted for 3 months. However, severe fibrous tissue proliferation was observed in the vitreous cavity and retrolental space of the third patient's eye, which led to tractional retinal detachment (TRD), iris neovascularization and formation of mature cataract. Injection of this patient's MSCs into the vitreous cavity of mice also resulted in fibrosis; however, intravitreal injections of the two other patients' cells into the mouse vitreous did not generate any fibrous tissue. CONCLUSION: Intravitreal injection of autologous bone marrow MSCs into patients' eyes with advanced RP does not meet safety standards. Major side effects of this therapy can include fibrosis and TRD. We propose thorough evaluation of MSCs prior to transplantation by intravitreal injection in the laboratory animals.\.

Mistletoe infestation mediates alteration of the phytohormone profile and anti-oxidative metabolism in bark and wood of its host Pinus sylvestris.

European mistletoe (Viscum album L.) has largely infested Central European forests and causes high mortality probability particularly in dry years. However, little information is available about the consequences of mistletoe infestation for metabolic processes in bark and wood of its host, despite their important roles in infestation defense. We analyzed the tissue hydration, carbohydrate composition, phytohormone profile, reactive oxygen species and anti-oxidant levels in bark and wood of Scots pines (Pinus sylvestris L.), as dependent on mistletoe infestation. As a consequence of mistletoe infestation, host bark and wood showed impaired hydration and reduced total carbon content. In the bark, soluble sugar and lignin contents increased, apparently at the expense of holo-cellulose. Hydrogen peroxide accumulation was accompanied by increased glutathione and decreased reduced ascorbic acid levels. Mistletoe infestation mediated alteration of the phytohormone profile in bark and wood of its host. Cytokinins, jasmonic acid and abscisic acid levels increased in both tissues, whereas salicylic acid and indole-3-acetic acid, which were only detected in the bark, declined. The present results show that mistletoe infestation affects both the host's anti-oxidative defense system and the phytohormone profile after establishment of the xylem tapping haustorium. The significance of these processes for the development of the woody mistletoe stem and the haustorium is discussed.

Safety and Efficacy of Repeated Bone Marrow Mononuclear Cell Therapy in Patients with Critical Limb Ischemia in a Pilot Randomized Controlled Trial.

BACKGROUND: Critical limb ischemia is a manifestation of peripheral arterial disease characterized by insufficient arterial blood flow for maintaining tissue viability in the lower extremities. Therapeutic angiogenesis is used for peripheral arterial disease patients who are not candidates for surgical revascularization or radiological intervention. There is accumulating evidence for the beneficial impact of autologous bone marrow mononuclear cell transplantation for treatment of critical limb ischemia in humans. This study aims to investigate the safety and efficacy of repeated bone marrow mononuclear cell injections in comparison with a single bone marrow mononuclear cell injection in critical limb ischemia patients. METHODS: Patients with critical limb ischemia (n = 22) were randomized (http://clinicaltrials.gov/ct2 show/NCT01480414) to receive either a single (n = 11) or four (n = 11) intramuscular injections of bone marrow mononuclear cells as a cell therapy product. RESULTS: There were no reported adverse events during the 24-week follow-up period after cell delivery. Efficacy assessment indicated that after cell injections, there was significant improvement in Ankle-Brachial Index, Visual Analog Scale, pain-free walking distance, and Wagner stage as well as reduction in ulcer size. There was no significant difference between the two groups in terms of clinical parameters. However, by the 24th week the pain-free walking distance improved significantly in the group who received four injections of cells. CONCLUSION: Favorable clinical outcomes strongly indicate the long-term benefit of bone marrow mononuclear cell transplantation, either as one or several injections, for retrieval from critical limb ischemia. Repeated cell injections have shown increased improvement of pain-free walking distance in patients. These findings warrant further exploration in later-phase clinical trials with repeated injections.

Intrathecal injection of CD133-positive enriched bone marrow progenitor cells in children with cerebral palsy: feasibility and safety.

BACKGROUND AIMS: Recent studies have proposed that cellular transplantation may have some regenerative and functional efficacy in the treatment of cerebral palsy (CP); however, much remains to be understood regarding its safety, feasibility and efficacy. This study was initiated to evaluate the safety of autologous bone marrow-derived CD133(+) cell intrathecal injection. METHODS: Children (n = 12), aged 4 to 12 years, who were diagnosed with different types of CP underwent BM aspiration. CD133(+) cells were enriched from the BM samples and intrathecally injected. The Gross Motor Function Measure (GMFM-66), Gross Motor Function Classification System (GMFCS), UK FIM+FAM, Functional Independence Measure (FIM) and Functional Assessment Measure (FAM) were assessed at baseline and 6 months after the procedure. Patients' ability to balance was measured by the Berg Balance Scale (BBS), and severity of spasticity was evaluated by the Modified Ashworth Scale. Magnetic resonance imaging was done at baseline and 6 months after therapy. This study was registered in ClinicalTrials.gov (NCT01404663). RESULTS: There were no adverse events detected by clinical and laboratory tests or imaging studies, with the exception of a seizure in 1 patient. A significant improvement was observed 6 months after cell transplantation versus baseline according to GMFM, GMFCS, FIM+FAM, Ashworth Scale, and BBS outcomes. CONCLUSIONS: Subarachnoid injection of CD133-positive enriched bone marrow progenitor cells in children with CP is a safe approach. The results suggest a possible short-term improvement in neurological function.