Cell therapies for heart function recovery: focus on myocardial tissue engineering and nanotechnologies

Cell therapies have gained increasing interest and developed in several approaches related to the treatment of damaged myocardium. The results of multiple clinical trials have already been reported, almost exclusively involving the direct injection of stem cells. It has, however, been postulated that the efficiency of injected cells could possibly be hindered by the mechanical trauma due to the injection and their low survival in the hostile environment. It has indeed been demonstrated that cell mortality due to the injection approaches 90%. Major issues still need to be resolved and bed-to-bench followup is paramount to foster clinical implementations. The tissue engineering approach thus constitutes an attractive alternative since it provides the opportunity to deliver a large number of cells that are already organized in an extracellular matrix. Recent laboratory reports confirmed the interest of this approach and already encouraged a few groups to investigate it in clinical studies. We discuss current knowledge regarding engineered tissue for myocardial repair or replacement and in particular the recent implementation of nanotechnological approaches.

Interhemispheric cerebral blood flow balance during recovery of motor hand function after ischemic stroke - a longitudinal MRI study using arterial spin labeling perfusion

BACKGROUND Unilateral ischemic stroke disrupts the well balanced interactions within bilateral cortical networks. Restitution of interhemispheric balance is thought to contribute to post-stroke recovery. Longitudinal measurements of cerebral blood flow (CBF) changes might act as surrogate marker for this process. OBJECTIVE To quantify longitudinal CBF changes using arterial spin labeling MRI (ASL) and interhemispheric balance within the cortical sensorimotor network and to assess their relationship with motor hand function recovery. METHODS Longitudinal CBF data were acquired in 23 patients at 3 and 9 months after cortical sensorimotor stroke and in 20 healthy controls using pulsed ASL. Recovery of grip force and manual dexterity was assessed with tasks requiring power and precision grips. Voxel-based analysis was performed to identify areas of significant CBF change. Region-of-interest analyses were used to quantify the interhemispheric balance across nodes of the cortical sensorimotor network. RESULTS Dexterity was more affected, and recovered at a slower pace than grip force. In patients with successful recovery of dexterous hand function, CBF decreased over time in the contralesional supplementary motor area, paralimbic anterior cingulate cortex and superior precuneus, and interhemispheric balance returned to healthy control levels. In contrast, patients with poor recovery presented with sustained hypoperfusion in the sensorimotor cortices encompassing the ischemic tissue, and CBF remained lateralized to the contralesional hemisphere. CONCLUSIONS Sustained perfusion imbalance within the cortical sensorimotor network, as measured with task-unrelated ASL, is associated with poor recovery of dexterous hand function after stroke. CBF at rest might be used to monitor recovery and gain prognostic information.

Baclofen facilitates sleep, neuroplasticity, and recovery after stroke in rats.

OBJECTIVE Sleep disruption in the acute phase after stroke has detrimental effects on recovery in both humans and animals. Conversely, the effect of sleep promotion remains unclear. Baclofen (Bac) is a known non-rapid eye movement (NREM) sleep-promoting drug in both humans and animals. The aim of this study was to investigate the effect of Bac on stroke recovery in a rat model of focal cerebral ischemia (isch). METHODS Rats, assigned to three experimental groups (Bac/isch, saline/isch, or Bac/sham), were injected twice daily for 10 consecutive days with Bac or saline, starting 24 h after induction of stroke. The sleep-wake cycle was assessed by EEG recordings and functional motor recovery by single pellet reaching test (SPR). In order to identify potential neuroplasticity mechanisms, axonal sprouting and neurogenesis were evaluated. Brain damage was assessed by Nissl staining. RESULTS Repeated Bac treatment after ischemia affected sleep, motor function, and neuroplasticity, but not the size of brain damage. NREM sleep amount was increased significantly during the dark phase in Bac/isch compared to the saline/isch group. SPR performance dropped to 0 immediately after stroke and was recovered slowly thereafter in both ischemic groups. However, Bac-treated ischemic rats performed significantly better than saline-treated animals. Axonal sprouting in the ipsilesional motor cortex and striatum, and neurogenesis in the peri-infarct region were significantly increased in Bac/isch group. CONCLUSION Delayed repeated Bac treatment after stroke increased NREM sleep and promoted both neuroplasticity and functional outcome. These data support the hypothesis of the role of sleep as a modulator of poststroke recovery.

A Thalamic-Fronto-Parietal Structural Covariance Network Emerging in the Course of Recovery from Hand Paresis after Ischemic Stroke.

AIM To describe structural covariance networks of gray matter volume (GMV) change in 28 patients with first-ever stroke to the primary sensorimotor cortices, and to investigate their relationship to hand function recovery and local GMV change. METHODS Tensor-based morphometry maps derived from high-resolution structural images were subject to principal component analyses to identify the networks. We calculated correlations between network expression and local GMV change, sensorimotor hand function and lesion volume. To verify which of the structural covariance networks of GMV change have a significant relationship to hand function, we performed an additional multivariate regression approach. RESULTS Expression of the second network, explaining 9.1% of variance, correlated with GMV increase in the medio-dorsal (md) thalamus and hand motor skill. Patients with positive expression coefficients were distinguished by significantly higher GMV increase of this structure during stroke recovery. Significant nodes of this network were located in md thalamus, dorsolateral prefrontal cortex, and higher order sensorimotor cortices. Parameter of hand function had a unique relationship to the network and depended on an interaction between network expression and lesion volume. Inversely, network expression is limited in patients with large lesion volumes. CONCLUSION Chronic phase of sensorimotor cortical stroke has been characterized by a large scale co-varying structural network in the ipsilesional hemisphere associated specifically with sensorimotor hand skill. Its expression is related to GMV increase of md thalamus, one constituent of the network, and correlated with the cortico-striato-thalamic loop involved in control of motor execution and higher order sensorimotor cortices. A close relation between expression of this network with degree of recovery might indicate reduced compensatory resources in the impaired subgroup.

A smooth transition protocol for patients with multifocal motor neuropathy going from intravenous to subcutaneous immunoglobulin therapy: an open-label proof-of-concept study

Intravenous immunoglobulin (IVIG) is the first-line therapy for multifocal motor neuropathy (MMN). This open-label multi-centre study (NCT00701662) assessed the efficacy, safety, and convenience of subcutaneous immunoglobulin (SCIG) in patients with MMN over 6 months, as an alternative to IVIG. Eight MMN patients (42-66 years), on stable IVIG dosing, received weekly SCIG at doses equivalent to previous IVIG using a "smooth transition protocol". Primary efficacy endpoint was the change from baseline to week 24 in muscle strength. Disability, motor function, and health-related quality of life (HRQL) endpoints were also assessed. One patient deteriorated despite dose increase and was withdrawn. Muscle strength, disability, motor function, and health status were unchanged in all seven study completers who rated home treatment as extremely good. Four experienced 18 adverse events, of which only two were moderate. This study suggests that MMN patients with stable clinical course on regular IVIG can be switched to SCIG at the same monthly dose without deterioration and with a sustained overall improvement in HRQL.

Lesions to primary sensory and posterior parietal cortices impair recovery from hand paresis after stroke

Neuroanatomical determinants of motor skill recovery after stroke are still poorly understood. Although lesion load onto the corticospinal tract is known to affect recovery, less is known about the effect of lesions to cortical sensorimotor areas. Here, we test the hypothesis that lesions of somatosensory cortices interfere with the capacity to recover motor skills after stroke.

Subcortical electrostimulation to identify network subserving motor control

Objectives: Recent anatomical-functional studies have transformed our understanding of cerebral motor control away from a hierarchical structure and toward parallel and interconnected specialized circuits. Subcortical electrical stimulation during awake surgery provides a unique opportunity to identify white matter tracts involved in motor control. For the first time, this study reports the findings on motor modulatory responses evoked by subcortical stimulation and investigates the cortico-subcortical connectivity of cerebral motor control. Experimental design: Twenty-one selected patients were operated while awake for frontal, insular, and parietal diffuse low-grade gliomas. Subcortical electrostimulation mapping was used to search for interference with voluntary movements. The corresponding stimulation sites were localized on brain schemas using the anterior and posterior commissures method. Principal observations: Subcortical negative motor responses were evoked in 20/21 patients, whereas acceleration of voluntary movements and positive motor responses were observed in three and five patients, respectively. The majority of the stimulation sites were detected rostral of the corticospinal tract near the vertical anterior-commissural line, and additional sites were seen in the frontal and parietal white matter. Conclusions: The diverse interferences with motor function resulting in inhibition and acceleration imply a modulatory influence of the detected fiber network. The subcortical stimulation sites were distributed veil-like, anterior to the primary motor fibers, suggesting descending pathways originating from premotor areas known for negative motor response characteristics. Further stimulation sites in the parietal white matter as well as in the anterior arm of the internal capsule indicate a large-scale fronto-parietal motor control network. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.

IVIg dose increase in multifocal motor neuropathy: a prospective six month follow-up

In this prospective, non-randomized 6-month observational study we evaluated the efficacy of intravenous immunoglobulin (IVIg) dose increase in patients with multifocal motor neuropathy (MMN). Diagnosis according to AAEM criteria, repetitive IVIg treatment for at least one year, persistent paresis and conduction block, stable symptoms and findings for at least six months were inclusion criteria. Nine patients (7 men) were identified and approved to standardized increase of IVIg dose. Patients were monitored using clinical scores and electrophysiological studies. Dose was increased from a baseline of 0.5 g/kg per month [mean, range: 0.1-1.1], given at variable intervals [4-12 weeks] to 1.2 g/kg per month given over 3 consecutive days planned for 6 cycles. If the patients' motor function did not improve after two cycles they entered step two: Dose was increased to 2 g/kg per month given over 5 consecutive days. The increased dose was maintained for 6 months. Assessments were performed by the same investigator, not involved in the patient's management, at baseline, after 2 and after 6 months. Following dose increase, motor function significantly improved in 6 patients (p = 0.014), 2 patients entered step two, 1 patient withdrew due to absent efficacy. Higher doses of IVIg caused more side effects, however, transient and rarely severe (p = 0.014). IVIg dose increase may improve motor functions in patients with stable MMN on long-term IVIg therapy independent of baseline dose. Improvement of motor function was associated with shorter disease duration (p = 0.008), but not with degree of muscle atrophy (p = 0.483). The treatment strategy to try to find the lowest effective dose and the longest tolerated interval might lead to underdosing in the long-term in many patients.

Enhancing rehabilitation of motor deficits with peripheral nerve stimulation

A number of different neurorehabilitation strategies include manipulation of the somatosensory system, e.g. in the form of training by passive movement. Recently, peripheral electrical nerve stimulation has been proposed as a simple, painless method of enhancing rehabilitation of motor deficits. Several physiological studies both in animals and in humans indicate that a prolonged period of patterned peripheral electrical stimulation induces short-term plasticity at multiple levels of the motor system. Small-scale studies in humans indicate that these plastic changes are linked with improvement in motor function, particularly in patients with chronic motor deficits after stroke. Somatosensory-mediated disinhibition of motor pathways is a possible underlying mechanism and might explain why peripheral electrical stimulation is more effective when combined with active training. Further large-scale studies are needed to identify the optimal stimulation protocol and the patient groups that stand to benefit the most from this technique.

Impact of Baseline Renal Function on Tenofovir-containing Antiretroviral Therapy Outcomes in Zambia

Background. Although tenofovir (TDF) use has increased as part of first-line antiretroviral therapy (ART) across sub-Saharan Africa, renal outcomes among patients receiving TDF remain poorly understood. We assessed changes in renal function and mortality in patients starting TDF- or non-TDF-containing ART in Lusaka, Zambia. Methods. We included patients aged ≥16 years who started ART from 2007 onward, with documented baseline weight and serum creatinine. Renal dysfunction was categorized as mild (eGFR 60-89 mL/min), moderate (30-59 mL/min) or severe (<30 mL/min) using the CKD-EPI formula. Differences in eGFR during ART were analyzed using linear mixed-effect models, the odds of developing moderate or severe eGFR decrease with logistic regression and mortality with competing risk regression. Results. We included 62,230 adults, of which 38,716 (62%) initiated a TDF-based regimen. The proportion with moderate or severe renal dysfunction at baseline was lower in the TDF compared to the non-TDF group (1.9% vs. 4.0%). Among patients with no or mild renal dysfunction, those on TDF were more likely to develop moderate (adjusted OR: 3.11; 95%CI: 2.52-3.87) or severe eGFR decrease (adjusted OR: 2.43; 95%CI: 1.80-3.28), although the incidence of such episodes was low. Among patients with moderate or severe renal dysfunction at baseline, renal function improved independently of ART regimen and mortality was similar in both treatment groups. Conclusions. TDF use did not attenuate renal function recovery or increase mortality in patients with renal dysfunction. Further studies are needed to determine the role of routine renal function monitoring before and during ART use in Africa.

Dysfunctions of the motor system in schizophrenia

Objective: Schizophrenia patients suffer from a variety of motor symptoms, including parkinsonism, catatonia, neurological soft signs, abnormal involuntary movements and psychomotor slowing. Methods: Literature review of prevalence rates and presentation of own results. Results: Parkinsonism and abnormal involuntary movements are intrinsic to schizophrenia, but may also be evoked by antipsychotic treatment. Reduced motor activity is associated with negative symptoms, catatonia and psychomotor slowing. Furthermore, 40 % of schizophrenia patients are impaired in gesture performance, which is related to executive and basic motor function. Mild motor disturbances are found in the majority of patients, while severe dysfunctions are limited to a minority. Our neuroimaging studies suggest that hypokinesia is caused by defective cortico-subcortical motor loops in schizophrenia. Taken together, a dimensional approach to schizophrenia motor symptoms seems promising. A purely descriptive assessment of motor signs is preferred over theoryladen categorization. Using objective motor parameters allows finding neural correlates of abnormal motor behaviour. Conclusion: The motor dimension of schizophrenia is linked to distinct disturbances in the cerebral motor system. Targeted modification of the defective motor system might become a relevant treatment option in patients suffering from schizophrenia with predominant motor features.

Highly efficient ketone body treatment in multiple acyl-CoA dehydrogenase deficiency-related leukodystrophy.

BACKGROUND Multiple acyl-CoA dehydrogenase deficiency- (MADD-), also called glutaric aciduria type 2, associated leukodystrophy may be severe and progressive despite conventional treatment with protein- and fat-restricted diet, carnitine, riboflavin, and coenzyme Q10. Administration of ketone bodies was described as a promising adjunct, but has only been documented once. METHODS We describe a Portuguese boy of consanguineous parents who developed progressive muscle weakness at 2.5 y of age, followed by severe metabolic decompensation with hypoglycaemia and coma triggered by a viral infection. Magnetic resonance (MR) imaging showed diffuse leukodystrophy. MADD was diagnosed by biochemical and molecular analyses. Clinical deterioration continued despite conventional treatment. Enteral sodium D,L-3-hydroxybutyrate (NaHB) was progressively introduced and maintained at 600 mg/kg BW/d (≈3% caloric need). Follow up was 3 y and included regular clinical examinations, biochemical studies, and imaging. RESULTS During follow up, the initial GMFC-MLD (motor function classification system, 0 = normal, 6 = maximum impairment) level of 5-6 gradually improved to 1 after 5 mo. Social functioning and quality of life recovered remarkably. We found considerable improvement of MR imaging and spectroscopy during follow up, with a certain lag behind clinical recovery. There was some persistent residual developmental delay. CONCLUSION NaHB is a highly effective and safe treatment that needs further controlled studies.

Intraoperative monopolar mapping during 5-ALA-guided resections of glioblastomas adjacent to motor eloquent areas: evaluation of resection rates and neurological outcome.

OBJECT Resection of glioblastoma adjacent to motor cortex or subcortical motor pathways carries a high risk of both incomplete resection and postoperative motor deficits. Although the strategy of maximum safe resection is widely accepted, the rates of complete resection of enhancing tumor (CRET) and the exact causes for motor deficits (mechanical vs vascular) are not always known. The authors report the results of their concept of combining monopolar mapping and 5-aminolevulinic acid (5-ALA)-guided surgery in patients with glioblastoma adjacent to eloquent tissue. METHODS The authors prospectively studied 72 consecutive patients who underwent 5-ALA-guided surgery for a glioblastoma adjacent to the corticospinal tract (CST; < 10 mm) with continuous dynamic monopolar motor mapping (short-train interstimulus interval 4.0 msec, pulse duration 500 μsec) coupled to an acoustic motor evoked potential (MEP) alarm. The extent of resection was determined based on early (< 48 hours) postoperative MRI findings. Motor function was assessed 1 day after surgery, at discharge, and at 3 months. RESULTS Five patients were excluded because of nonadherence to protocol; thus, 67 patients were evaluated. The lowest motor threshold reached during individual surgery was as follows (motor threshold, number of patients): > 20 mA, n = 8; 11-20 mA, n = 13; 6-10 mA, n = 10; 4-5 mA, n = 13; and 1-3 mA, n = 23. Motor deterioration at postsurgical Day 1 and at discharge occurred in 30% (n = 20) and 10% (n = 7) of patients, respectively. At 3 months, 3 patients (4%) had a persisting postoperative motor deficit, 2 caused by vascular injury and 1 by mechanical injury. The rates of intra- and postoperative seizures were 1% and 0%, respectively. Complete resection of enhancing tumor was achieved in 73% of patients (49/67) despite proximity to the CST. CONCLUSIONS A rather high rate of CRET can be achieved in glioblastomas in motor eloquent areas via a combination of 5-ALA for tumor identification and intraoperative mapping for distinguishing between presumed and actual motor eloquent tissues. Continuous dynamic mapping was found to be a very ergonomic technique that localizes the motor tissue early and reliably.

Continuous dynamic mapping of the corticospinal tract during surgery of motor eloquent brain tumors: evaluation of a new method

OBJECT The authors developed a new mapping technique to overcome the temporal and spatial limitations of classic subcortical mapping of the corticospinal tract (CST). The feasibility and safety of continuous (0.4-2 Hz) and dynamic (at the site of and synchronized with tissue resection) subcortical motor mapping was evaluated. METHODS The authors prospectively studied 69 patients who underwent tumor surgery adjacent to the CST (< 1 cm using diffusion tensor imaging and fiber tracking) with simultaneous subcortical monopolar motor mapping (short train, interstimulus interval 4 msec, pulse duration 500 μsec) and a new acoustic motor evoked potential alarm. Continuous (temporal coverage) and dynamic (spatial coverage) mapping was technically realized by integrating the mapping probe at the tip of a new suction device, with the concept that this device will be in contact with the tissue where the resection is performed. Motor function was assessed 1 day after surgery, at discharge, and at 3 months. RESULTS All procedures were technically successful. There was a 1:1 correlation of motor thresholds for stimulation sites simultaneously mapped with the new suction mapping device and the classic fingerstick probe (24 patients, 74 stimulation points; r(2) = 0.98, p < 0.001). The lowest individual motor thresholds were as follows: > 20 mA, 7 patients; 11-20 mA, 13 patients; 6-10 mA, 8 patients; 4-5 mA, 17 patients; and 1-3 mA, 24 patients. At 3 months, 2 patients (3%) had a persistent postoperative motor deficit, both of which were caused by a vascular injury. No patient had a permanent motor deficit caused by a mechanical injury of the CST. CONCLUSIONS Continuous dynamic mapping was found to be a feasible and ergonomic technique for localizing the exact site of the CST and distance to the motor fibers. The acoustic feedback and the ability to stimulate the tissue continuously and exactly at the site of tissue removal improves the accuracy of mapping, especially at low (< 5 mA) stimulation intensities. This new technique may increase the safety of motor eloquent tumor surgery.

Addition of magnesium sulphate to ropivacaine for spinal analgesia in dogs undergoing tibial plateau levelling osteotomy

The aim of this blinded, randomised, prospective clinical trial was to determine whether the addition of magnesium sulphate to spinally-administered ropivacaine would improve peri-operative analgesia without impairing motor function in dogs undergoing orthopaedic surgery. Twenty client-owned dogs undergoing tibial plateau levelling osteotomy were randomly assigned to one of two treatment groups: group C (control, receiving hyperbaric ropivacaine by the spinal route) or group M (magnesium, receiving a hyperbaric combination of magnesium sulphate and ropivacaine by the spinal route). During surgery, changes in physiological variables above baseline were used to evaluate nociception. Arterial blood was collected before and after spinal injection, at four time points, to monitor plasma magnesium concentrations. Post-operatively, pain was assessed with a modified Sammarco pain score, a Glasgow pain scale and a visual analogue scale, while motor function was evaluated with a modified Tarlov scale. Assessments were performed at recovery and 1, 2 and 3 h thereafter. Fentanyl and buprenorphine were administered as rescue analgesics in the intra- and post-operative periods, respectively. Plasma magnesium concentrations did not increase after spinal injection compared to baseline. Group M required less intra-operative fentanyl, had lower Glasgow pain scores and experienced analgesia of longer duration than group C (527.0 ± 341.0 min vs. 176.0 ± 109.0 min). However, in group M the motor block was significantly longer, which limits the usefulness of magnesium for spinal analgesia at the investigated dose. Further research is needed to determine a clinically effective dose with shorter duration of motor block for magnesium used as an additive to spinal analgesic agents.