Progress and prospects in neurorehabilitation: clinical applications of stem cells and brain–computer interface for spinal cord lesions

Spinal cord injury (SCI) is a disease that affects millions of people worldwide, causing a temporary or permanent impairment of neuromotor functions. Mostly associated to traumatic lesions, but also to other forms of disease, the appropriate treatment is still unsure. In this review, several ongoing studies are presented that aim to provide methods of prevention that ensure quality of life, and rehabilitation trends to patients who suffer from this injury. Stem cell research, highlighted in this review, seeks to reduce damage caused to the tissue, as also provide spinal cord regeneration through the application of several types of stem cells. On the other hand, research using brain–computer interface (BCI) technology proposes the development of interfaces based on the interaction of neural networks with artificial tools to restore motor control and full mobility of the injured area. PubMed, MEDLINE and SciELO data basis analyses were performed to identify studies published from 2000 to date, which describe the link between SCI with stem cells and BCI technology.     

An investigation of the potential application of chitosan/aloe-based membranes for regenerative medicine

A significant number of therapeutics derived from natural polymers and plants have been developed to replace or to be used in conjunction with existing dressing products. The use of the therapeutic properties of aloe vera could be very useful in the creation of active wound dressing materials. The present work was undertaken to examine issues concerning structural features, topography, enzymatic degradation behavior, antibacterial activity and cellular response of chitosan/aloe vera-based membranes. The chitosan/aloe vera-based membranes that were developed displayed satisfactory degradation, roughness, wettability and mechanical properties. A higher antibacterial potency was displayed by the blended membranes. Moreover, in vitro assays demonstrated that these blended membranes have good cell compatibility with primary human dermal fibroblasts. The chitosan/aloe vera-based membranes might be promising wound dressing materials.     

Methadone in post-herpetic neuralgia: A pilot proof-of-concept study

OBJECTIVE:

This research was designed as a pilot proof-of-concept study to evaluate the use of low-dose methadone in post-herpetic neuralgia patients who remained refractory after first and second line post-herpetic neuralgia treatments and had indications for adding an opioid agent to their current drug regimens.

METHODS:

This cross-over study was double blind and placebo controlled. Ten opioid naïve post-herpetic neuralgia patients received either methadone (5 mg bid) or placebo for three weeks, followed by a 15-day washout period and a second three-week treatment with either methadone or placebo, accordingly. Clinical evaluations were performed four times (before and after each three-week treatment period). The evaluations included the visual analogue scale, verbal category scale, daily activities scale, McGill pain questionnaire, adverse events profile, and evoked pain assessment. All patients provided written informed consent before being included in the study. ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01752699","term_id":"NCT01752699"}}NCT01752699

RESULTS:

Methadone, when compared to placebo, did not significantly affect the intensity of spontaneous pain, as measured by the visual analogue scale. The intensity of spontaneous pain was significantly decreased after the methadone treatment compared to placebo on the category verbal scale (50% improved after the methadone treatment, none after the placebo, p = 0.031). Evoked pain was reduced under methadone compared to placebo (50% improved after the methadone treatment, none after the placebo, p = 0.031). Allodynia reduction correlated with sleep improvement (r = 0.67, p = 0.030) during the methadone treatment. The side effects profile was similar between both treatments.

CONCLUSIONS:

Methadone seems to be safe and efficacious in post-herpetic neuralgia. It should be tried as an adjunctive treatment for post-herpetic neuralgia in larger prospective studies.     

Blockade of CXCR1/2 chemokine receptors protects against brain damage in ischemic stroke in mice: Ischemia and Reparixin

OBJECTIVE:

Ischemic stroke may result from transient or permanent reductions of regional cerebral blood flow. Polymorphonuclear neutrophils have been described as the earliest inflammatory cells to arrive in ischemic tissue. CXCR1/2 receptors are involved in the recruitment of these cells. However, the contribution of these chemokine receptors during transient brain ischemia in mice remains poorly understood. In this work, we investigated the effects of reparixin, an allosteric antagonist of CXCR1/2 receptors, in a model of middle cerebral artery occlusion and reperfusion in mice.

METHODS:

C57BL/6J male mice treated with reparixin or vehicle were subjected to a middle cerebral artery occlusion procedure 1 h after the treatment. Ninety minutes after ischemia induction, the monofilament that prevented blood flow was removed. Twenty-four hours after the reperfusion procedure, behavioral changes, including motor signs, were analyzed with the SmithKline/Harwell/Imperial College/Royal Hospital/Phenotype Assessment (SHIRPA) battery. The animals were sacrificed, and brain tissue was removed for histological and biochemical analyses. Histological sections were stained with hematoxylin and eosin, neutrophil infiltration was estimated by myeloperoxidase activity and the inflammatory cytokine IL-1β was measured by ELISA.

RESULTS:

Pre-treatment with reparixin reduced the motor deficits observed in this model of ischemia and reperfusion. Myeloperoxidase activity and IL-1β were reduced in the reparixin-treated group. Histological analysis revealed that ischemic injury was also attenuated by reparixin pre-treatment.

CONCLUSIONS:

Our results suggest that the blockade of the CXCR1/2 receptors by reparixin promotes neuroprotective effects by reducing the levels of polymorphonuclear infiltration in the brain and the tissue damage associated with middle cerebral artery occlusion and reperfusion.     

Myeloid-derived suppressor cells and associated events in urethane-induced lung cancer

OBJECTIVES:

Myeloid-derived suppressor cells contribute to the immunosuppressive microenvironment during tumor development and limit the efficacy of cancer immunotherapy. Identifying myeloid-derived suppressor cells and associated factors is the first step in creating strategies to reverse the suppressive effects of these cells on the immune system.

METHODS:

To induce lung cancer, we administered 2 doses of urethane to BALB/c mice and observed these animals for 120 days. After this period, we evaluated the percentage of myeloid-derived suppressor cells in the blood, lung and bone marrow. The expression of alpha-smooth muscle actin, transforming growth factor-β, Toll-like receptor 2, Toll-like receptor 4, and interleukin-6 was also determined in the lung tissue.

RESULTS:

Myeloid-derived suppressor cells were increased in all evaluated tissues after lung cancer development in association with increased Toll-like receptor 4 expression and decreased interleukin-6 expression in the lung. We observed alpha-smooth muscle actin and transforming growth factor-β expression in lung nodules.

CONCLUSIONS:

We believe that the early diagnosis of cancer through determining the blood levels of myeloid-derived suppressor cells followed by the depletion of these cells should be further investigated as a possible approach for cancer treatment.     

Immunogenicity of Recombinant Proteins Consisting of Plasmodium vivax Circumsporozoite Protein Allelic Variant-Derived Epitopes Fused with Salmonella enterica Serovar Typhimurium Flagellin

A Plasmodium falciparum circumsporozoite protein (CSP)-based recombinant fusion vaccine is the first malaria vaccine to reach phase III clinical trials. Resistance to infection correlated with the production of antibodies to the immunodominant central repeat region of the CSP. In contrast to P. falciparum, vaccine development against the CSP of Plasmodium vivax malaria is far behind. Based on this gap in our knowledge, we generated a recombinant chimeric protein containing the immunodominant central repeat regions of the P. vivax CSP fused to Salmonella enterica serovar Typhimurium-derived flagellin (FliC) to activate the innate immune system. The recombinant proteins that were generated contained repeat regions derived from each of the 3 different allelic variants of the P. vivax CSP or a fusion of regions derived from each of the 3 allelic forms. Mice were subcutaneously immunized with the fusion proteins alone or in combination with the Toll-like receptor 3 (TLR-3) agonist poly(I·C), and the anti-CSP serum IgG response was measured. Immunization with a mixture of the 3 recombinant proteins, each containing immunodominant epitopes derived from a single allelic variant, rather than a single recombinant protein carrying a fusion of regions derived from each of 3 allelic forms elicited a stronger immune response. This response was independent of TLR-4 but required TLR-5/MyD88 activation. Antibody titers significantly increased when poly(I·C) was used as an adjuvant with a mixture of the 3 recombinant proteins. These recombinant fusion proteins are novel candidates for the development of an effective malaria vaccine against P. vivax.     

Traumatic dental injury among 12‐year‐old South Brazilian schoolchildren: prevalence,severity, and risk indicators

Abstract – An increasing prevalence of traumatic dental injury (TDI) has been reported in the last few decades. The aim of this study was to assess the prevalence and severity of TDI and its association with socio‐demographics and physical characteristics in the anterior permanent teeth of 12‐year‐old Brazilian schoolchildren. A cross‐sectional study was carried out in a population‐based sample of 1528 subjects attending 33 public and nine private schools (response rate of 83.17%). A single calibrated examiner performed the clinical examinations at the schools and recorded the TDI index (Children’s Dental Health Survey criteria), overjet and lip coverage. Height and weight were measured to calculate the body mass index (BMI). Parents/legal guardians answered a questionnaire containing socio‐demographic questions. The relationships among TDI, socio‐demographic variables and physical characteristics were assessed by survey Poisson regression models. The prevalence of TDI was 34.79% (mild trauma = 24.37%; severe trauma = 10.43%). Male schoolchildren (RR = 1.41, 95% CI = 1.23–1.61, P = 0.002) and schoolchildren from low socioeconomic status (RR = 1.32, 95% CI = 1.07–1.64, P = 0.021) were more likely to present at least one tooth with TDI, whereas students attending 7th grade (advanced students) were less likely to experience TDI (RR = 0.59, 95% CI = 0.43–0.82, P = 0.012). Regarding the severity analysis, students of mid‐high (RR = 1.46, 95% CI = 1.09–1.94, P = 0.022), mid‐low (RR = 1.68, 95% CI = 1.01–2.77, P = 0.045) and low (RR = 1.78, 95% CI = 1.11–2.85, P = 0.027) socioeconomic status were more likely to have mild trauma when compared with schoolchildren of high socioeconomic status. No significant association between severe trauma and socioeconomic status was observed. In conclusion, this study showed a high prevalence of TDI in 12‐year‐old Brazilian schoolchildren. Socio‐demographic data and school achievement were associated with TDI.