Preclinical studies suggest that stem cells may be a valuable therapeutic tool in amyotrophic lateral sclerosis (ALS). As it has been demonstrated that there are molecular changes at the end-plate ...during the early stages of motorneuron degeneration in animal models, we hypothesize that the local effect of this stem cell delivery method could slow the progressive loss of motor units (MUs) in ALS patients.
We designed a Phase I/II clinical trial to study the safety of intramuscularly implanting autologous bone marrow mononuclear cells (BMMCs), including stem cells, in ALS patients and their possible effects on the MU of the tibialis anterior (TA) muscle. Twenty-two patients participated in a randomized, double-blind, placebo-controlled trial that consisted of a baseline visit followed by one intramuscular injection of BMNCs, follow-up visits at 30, 90, 180, and 360 days, and an additional year of clinical follow-up. In each patient, one TA muscle was injected with a single dose of BMMCs while the contralateral muscle was given a placebo; the sides were selected randomly. All visits included a complete EMG study of both TA muscles.
Our results show that (1) the intramuscular injection of BMMCs is a safe procedure; (2) ALS patients show heterogeneities in the degree of TA injury; (3) a comparison of placebo-injected muscles with BMMC-injected muscles showed significant differences in only one parameter, the D50 index used to quantify the Compound Muscle Action Potential (CMAP) scan curve. This parameter was higher in the BMMC-injected TA muscle at both 90 days (placebo side: 29.55 ± 2.89,
= 20; experimental side: 39.25 ± 3.21,
= 20;
< 0.01) and 180 days (placebo side: 29.35 ± 3.29,
= 17; experimental side: 41.24 ± 3.34,
= 17;
< 0.01).
This procedure had no effect on the TA muscle MU properties, with the exception of the D50 index. Finding differences in just this index supports the fact that it may be much more sensitive than other electrophysiological parameters when studying treatment effects. Given the low number of patients and their heterogeneity, these results justify exploring the efficacy of this procedure in further patients and other muscles, through Phase II trials.
www.clinicaltrials.gov (identifier NCT02286011); EudraCT number 2011-004801-25.
Abstract Background: Treatment with interferon-β (IFN-β) has been related to worsening of muscle spasticity in patients with multiple sclerosis (MS). However, there are no specific data on the ...effects of glatiramer acetate (GA) on spasticity. Objective: The aim of the present study was to assess the effects of GA on spasticity in patients with relapsing-remitting MS who had been previously treated with IFN-β or were treatment naive. Methods: Two cohorts of MS patients with spasticity who were about to begin treatment with GA at the approved dosage (20 mg/d) were enrolled in the study: patients who were being switched from IFN-β due to adverse events or lack of efficacy (cohort 1) and patients who were treatment naive (cohort 2). The follow-up periods for cohorts 1 and 2 were 18 and 12 months, respectively. Patients' physical condition was assessed at baseline and at the end of follow-up using the Modified Ashworth Scale (MAS), Penn Spasm Frequency Scale (PSFS), Global Pain Score (GPS), Adductor Tone Rating Scale, Expanded Disability Status Scale (EDSS), and neurophysiologic tests (latency and amplitude of the Hoffmann reflex H reflex in the soleus, and ratio of maximum H reflex to maximum motor response H/M ratio in the lower limb). The frequency and severity of adverse events were recorded throughout follow-up, and investigators rated the causal relationship to GA (unrelated, unlikely, possibly, or probably). Results: Twenty-eight patients were included in the study, 13 in cohort 1 and 15 in cohort 2. All patients were white. Cohort 1 was 76.9% female, with a mean (SD) age of 39.85 (9.25) years; cohort 2 was 66.7% female, with a mean age of 40.73 (11.52) years. Cohort 1 had significant reductions from baseline to the end of follow-up in mean scores on the MAS for the right hemibody (from 1.85 0.61 to 1.18 0.60; P = 0.002) and left hemibody (from 1.86 0.55 to 1.27 0.65; P = 0.045), PSFS (from 2.00 0.91 to 0.36 0.81; P = 0.002), and GPS (from 47.69 13.94 to 24.09 17.15 mm; P = 0.002). The changes from baseline were not significant on the mean Adductor Tone Rating Scale, EDSS, H-reflex latency or amplitude on either side, or lower-limb H/M ratio on either side. Cohort 2 had significant reductions from baseline in H-reflex latency on the left side (from 30.31 2.44 to 28.75 2.01; P = 0.005) and H/M ratio on the right side (from 0.45 0.15 to 0.35 0.19; P = 0.025). There were no significant changes in mean scores on the MAS for either hemibody, PSFS, GPS, Adductor Tone Rating Scale, EDSS, H-reflex latency on the right side, H-reflex amplitude on either side, or lower-limb H/M ratio on the left side. Sixteen patients experienced a total of 28 adverse events. Seven mild adverse events were considered related to GA: local reaction at the injection site (3 patients); headache/migraine, anxiety, and skin reaction (1 patient each); and an unspecified adverse drug reaction (1 patient). Two serious adverse events (pyelonephritis and pyrexia) occurred during the study, neither of them considered related to GA. Conclusions: In this pilot study in patients with relapsing-remitting MS, GA treatment did not increase spasticity. Furthermore, the results suggest that GA may reduce spasticity in patients previously treated with IFN-β. These findings support the conduct of large randomized controlled trials of the effects of GA on spasticity.
Highlights • It is a phase I clinical trial on amyotrophic lateral sclerosis that provides research in the field of security beyond the parameters of spirometry or usual scales. • If the patients ...diagnosed with ALS, spinal onset, and duration of disease <36 months have FVC > 50% of predicted, and sleep time oxygen saturation below 90% (T90) ≤2% during 6 months, it is likely that they have stability in breathing pattern 12 months after. • If the patients diagnosed with ALS, spinal onset, and duration of disease <36 months have FVC > 50% of predicted, and sleep time oxygen saturation below 90% (T90) ≤2% during 6 months, it is likely that they have REM sleep preserved 12 months after. • The spinal injection of of autologous bone marrow mononuclear cells in patients with amyotrophic lateral sclerosis is safe and it is possible in ALS patients without worsening the disease.
Abstract 4393
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterised by loss of motoneurons (mns), and it has no cure. Cell therapy has neurotrophic effects in animal ...models and has been proposed as a disease-modifying treatment. Our aim was twofold: firstly, to assess the safety of intraspinal infusion of bone marrow mononuclear cells (BMNC) and, ultimately, to look for histopathological signs of cellular neurotrophism.
We conducted an open single arm phase I trial. After six months observation, autologous BMNC were infused into the posterior spinal cord funiculus. Safety was the primary endpoint and was defined as the absence of serious transplant-related adverse events. In addition, forced vital capacity (FVC) and ALS-FRS, MRC and Norris scales were assessed six and three months prior to the transplant and quarterly afterwards for one year. Pathological studies were performed in case of death.
Eleven patients were included. We did not observe any severe transplant-related adverse event but there were 43 non-severe events. Twenty-two (51%) resolved in ≤2 weeks and only four were still present at the end of follow-up. All were CTCAE grade ≤2. No acceleration in the rate of decline of FVC, ALS-FRS, Norris or MRC scales was observed. Four patients died on days 359, 378, 808 and 1058 postransplant for reasons unrelated to the procedure. Spinal cord pathological analysis showed a greater number of montoneurons in the treated compared to the untreated segments (4.2+/−0.8 mns/section and 0.9+/−0.3 mns/section, respectively). In the treated segments, motoneurons were surrounded by CD90+ cells and did not show degenerative ubiquitin deposits.
This clinical trial confirms not only the safety of intraspinal infusion of autologous BMNC in ALS patients but also provides evidence of their neurotrophic activity.
No relevant conflicts of interest to declare.
Hirayama disease is a rare children's muscular atrophy that affects young Asian males, with muscular atrophy usually in one of the upper limbs that progresses slowly and later stabilises. It is ...diagnosed by means of electromyographic/electroneurographic with conduction speed studies (EMG/ENG-CS) and by magnetic resonance imaging (MRI) of the spinal cord in a neutral position and with cervical flexion. Treatment is based on the cervical collar and surgery (severe cases). Very few studies have been conducted on patients at the paediatric age.
We report the case of a 7-year-old girl with atrophy of the muscles of the left hand and forearm, and a disease history of two years. The EMG/ENG-CS scans presented signs of very severe chronic denervation in the myotomes of C7, C8 and T1 on the left side, with conservation of the amplitudes of sensory evoked potentials, consistent with cervical myelopathy. Results of an MRI scan of the cervical spinal cord in a neutral position were normal at that level. Later, owing to suspicions pointing towards Hirayama disease, a new MRI scan of the cervical spinal cord was performed in a neutral position and in flexion. This second scan showed asymmetry in the size and morphology of the anterior funiculi of the spinal cord at C6/C7, hypersignal in the homolateral anterior horn and ingurgitation of the posterior epidural venous plexus. With a diagnosis of Hirayama disease, treatment is started with a cervical collar in order to prevent the damage from getting worse.
This case of Hirayama disease is peculiar due to its epidemiological characteristics and is presented here with the aim of making this entity more widely known in our milieu. If diagnosed at an early stage, treatment is effective, and the studies conducted on children at the paediatric age are reviewed.
Background_ Treatment with interferon-β (IFN-β) has been related to worsening of muscle spasticity in patients with multiple sclerosis (MS). However, there are no specific data on the effects of ...glatiramer acetate (GA) on spasticity. Objective_ The aim of the present study was to assess the effects of GA on spasticity in patients with relapsing-remitting MS who had been previously treated with IFN-β or were treatment naive. Methods_ Two cohorts of MS patients with spasticity who were about to begin treatment with GA at the approved dosage (20 mg/d) were enrolled in the study: patients who were being switched from IFN-β due to adverse events or lack of efficacy (cohort 1) and patients who were treatment naive (cohort 2). The follow-up periods for cohorts 1 and 2 were 18 and 12 months, respectively. Patients' physical condition was assessed at baseline and at the end of follow-up using the Modified Ashworth Scale (MAS), Penn Spasm Frequency Scale (PSFS), Global Pain Score (GPS), Adductor Tone Rating Scale, Expanded Disability Status Scale (EDSS), and neurophysiologic tests (latency and amplitude of the Hoffmann reflex H reflex in the soleus, and ratio of maximum H reflex to maximum motor response H/M ratio in the lower limb). The frequency and severity of adverse events were recorded throughout follow-up, and investigators rated the causal relationship to GA (unrelated, unlikely, possibly, or probably). Results_ Twenty-eight patients were included in the study, 13 in cohort 1 and 15 in cohort 2. All patients were white. Cohort 1 was 76.9% female, with a mean (SD) age of 39.85 (9.25) years; cohort 2 was 66.7% female, with a mean age of 40.73 (11.52) years. Cohort 1 had significant reductions from baseline to the end of follow-up in mean scores on the MAS for the right hemibody (from 1.85 0.61 to 1.18 0.60; P = 0.002) and left hemibody (from 1.86 0.55 to 1.27 0.65; P = 0.045), PSFS (from 2.00 0.91 to 0.36 0.81; P = 0.002), and GPS (from 47.69 13.94 to 24.09 17.15 mm; P = 0.002). The changes from baseline were not significant on the mean Adductor Tone Rating Scale, EDSS, H-reflex latency or amplitude on either side, or lower-limb H/M ratio on either side. Cohort 2 had significant reductions from baseline in H-reflex latency on the left side (from 30.31 2.44 to 28.75 2.01; P = 0.005) and H/M ratio on the right side (from 0.45 0.15 to 0.35 0.19; P = 0.025). There were no significant changes in mean scores on the MAS for either hemibody, PSFS, GPS, Adductor Tone Rating Scale, EDSS, H-reflex latency on the right side, H-reflex amplitude on either side, or lower-limb H/M ratio on the left side. Sixteen patients experienced a total of 28 adverse events. Seven mild adverse events were considered related to GA: local reaction at the injection site (3 patients); headache/migraine, anxiety, and skin reaction (1 patient each); and an unspecified adverse drug reaction (1 patient). Two serious adverse events (pyelonephritis and pyrexia) occurred during the study, neither of them considered related to GA. Conclusions_ In this pilot study in patients with relapsing-remitting MS, GA treatment did not increase spasticity. Furthermore, the results suggest that GA may reduce spasticity in patients previously treated with IFN-β. These findings support the conduct of large randomized controlled trials of the effects of GA on spasticity.
Introducción: La infección postoperatoria es una posible complicación tras la exodoncia quirúrgica de los terceros molares. Se trata generalmente de infecciones de origen mixto, que pueden aparecer ...precoz o tardíamente, aumentando la morbilidad y retrasando la recuperación del paciente. Objetivo: Comprobar la eficacia de un antibiótico derivado de la penicilina, resistente a las betalactamasas; la sultamicilina (Sulbactam-Ampicilina), en la prevención de infecciones postoperatorias. Método: Se han extraído 476 terceros molares en 238 pacientes, administrándoles a todos ellos Sultamicilina antes y después de la intervención, evaluando y analizando estadísticamente diversas variables, durante un período de seguimiento de tres meses. Resultados: Hemos obtenido un índice de 0,63% de alveolitis, frente a índices, publicados por otros autores, que oscilan entre 0,5% a 30%. En las infecciones secundarias hallamos 0,42%, la incidencia más baja en la bibliografía revisada, que recoge unos índices comprendidos entre 1,5% a 5,8%. Conclusiones: Los excelentes resultados obtenidos, con uno de los índices más bajos publicados de alveolitis y el índice más bajo que hemos encontrado de infecciones secundarias, demuestran la eficacia de la Sultamicilina en la prevención de la aparición de complicaciones infecciosas tras la exodoncia de terceros molares incluidos.
•The calculation formulation of four international design guides for FRP strengthening of axially-loaded non-circular RC columns are evaluated.•The effect of the parameters h/b, Rc and kɛ on the ...mechanical behaviour is studied.•The comparison between the experimental data and the calculated results with guidelines has been undertaken.•The guides’ recommendations to set a minimum confinement ratio (CR) that guarantees an efficient confinement are analysed.
Several international guides offer recommendations for the calculation and design of reinforcements with fibre reinforced polymer (FRP) composites. To strengthen axially-loaded columns, the guides adopt design stress–strain models based on extensive research into small-scale specimens of plain concrete confined with FRP. However, through this type of testing, it is difficult to accurately predict the behaviour of existing full-scale reinforced concrete (RC) columns confined with FRP composites.
This paper presents a review of the formulation proposed by four international guides. The study compiles the available test results on medium and large-scale rectangular RC columns confined with carbon FRP composites subjected to axial compression concentric load.
The predictions of the axial strength and the ultimate strain of the FRP-confined concrete are compared to the experimental results. The minimum confinement ratio (CR) recommended in the guides to guarantee sufficient confinement level is also analysed, alongside the estimation of the effective strain in the CFRP jacket at failure. The results obtained have proven uneven.
The best predictions of the concrete strength improvement have been obtained with the ACI and fib guides. In general, to comply with the minimum CR proposed by the guides fails to prevent a softening stress–strain response, frequent in the rectangular tests analysed. The more restrictive CR criteria (from the CNR and fib guide) have shown themselves to be more suitable.
The ultimate strain of the confined concrete is underestimated by the guides and the errors obtained are much higher than in the prediction of the strength enhancement ratio.
Despite the widespread dispersion of the results, the mean value of strain efficiency factor obtained in the tests is similar to the value of 0.55 recommended by ACI. This parameter is not easy to determine for rectangular columns, but its estimation is essential for the calculation.
Several studies have independently evaluated the occurrence of hepatitis E virus (HEV) and enteroparasites in swine, but no surveys have been conducted to jointly assess the prevalence and genetic ...diversity of enteroparasites in pigs and wild boars, their sympatric transmission between hosts, and their potential interaction with HEV.
We prospectively collected serum and faecal samples from black Iberian domestic pigs and wild boars from southern Spain between 2015‒2016. We evaluated for HEV in serum and faeces, and for the presence of enteroparasites (Giardia duodenalis, Cryptosporidium spp., Blastocystis sp., Neobalantidium coli and Strongyloides spp.) in the same faecal samples. The prevalence of each intestinal parasite species was calculated.
A total of 328 animals (56.7% black Iberian pigs and 43.3% wild boars) were included in the study. The overall global prevalence of HEV in serum was 16.8%. The overall global prevalence of each enteroparasite species was 19.5% for G. duodenalis, 8.2% for Cryptosporidium spp., 41.8% for Blastocystis sp., 31.4% for N. coli, and 8.8% for Strongyloides spp. HEV-infected animals showed a significantly lower prevalence of G. duodenalis (3.2 vs 20%; P = 0.002) and Blastocystis sp. (38.7 vs 80%; P < 0.001) than those uninfected by HEV. Animals carrying G. duodenalis and Blastocystis sp. infections showed a significantly lower rate of HEV infection than those not harbouring these enteroparasites (P < 0.001).
Our study found a high prevalence of enteroparasites in black Iberian pigs and wild boars in southern Spain, suggesting a sympatric co-transmission of some of the species investigated. It is suggested that extracellular G. duodenalis and Blastocystis sp. might have a protective effect on HEV acquisition in swine.
This article proposes an optimized version of a canonical piece-wise-linear (CPWL) digital predistorter in order to enhance the linearity of a radio-over-fiber (RoF) LTE mobile fronthaul. In this ...work, we propose a threshold allocation optimization process carried out by a genetic algorithm (GA) in order to optimize the CPWL model (GA-CPWL). Firstly, experiments show how the CPWL model outperforms the classical memory polynomial DPD in an intensity modulation/direct detection (IM/DD) RoF link. Then, the GA-CPWL predistorter is compared with the CPWL model in several scenarios, in order to verify that the proposed DPD offers better performance in different optical transmission conditions. Experimental results reveal that with a proper threshold allocation, the GA-CPWL predistorter offers very promising outcomes.
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